GSK b2c109575 Clinical Study Report Redact PDF
GSK b2c109575 Clinical Study Report Redact PDF
GSK b2c109575 Clinical Study Report Redact PDF
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numbered
CONFIDENTIAL
CONFIDENTIAL
TheGlaxoSmithKline
GlaxoSmithKline
of companies
The
groupgroup
of companies
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
Phase:
IIb
27 April 2009
Description: This study evaluated the efficacy, safety and pharmacokinetics (PK) of five
doses of GW642444M and placebo in adult and adolescent subjects with persistent
asthma. Following Screening and a 14-day Run-in period, subjects meeting eligibility
criteria were stratified in an approximately 1:1 ratio according to their baseline FEV1
expressed as a percentage of predicted normal (40% - 65% or >65% - 90%).
Subjects were randomised to one of six double-blind 28-day treatments (GW642444M 3
g, 6.25 g, 12.5 g, 25 g, 50 g, or placebo) administered via the Novel Dry Powder
Inhaler once-daily in the evening. At the end of the treatment period, subjects entered a
seven-day Follow-up period. Once-daily treatment with GW642444M for 28 days
resulted in dose-dependent improvements in lung function, with 12.5 g, 25 g, 50 g
GW642444M showing statistically significant increases of up to 0.162 L from baseline
compared with placebo in trough FEV1, measured 23-24 h after the last dose on Day 28
(the primary efficacy endpoint). FEV1 improved in a similar manner across the strata
The improvements in FEV1 measurements were also seen across other secondary efficacy
parameters including morning and evening peak expiratory flow (PEF) and percentage of
symptom- and rescue-free 24-h periods with the greatest improvements seen with 25 g
and 50 g. All GW642444M doses were well-tolerated throughout the study period. The
incidence of adverse events (AEs) was similar across the GW642444M treatment groups
and was comparable with placebo. Headache was most frequently reported across all
groups. No serious adverse events (SAEs) were reported on study treatment. No safety
concerns were noted from haematology, clinical chemistry (including liver function tests)
and urinalysis, vital signs or glucose and potassium assessments. There were no
clinically relevant increases from baseline versus placebo in serial, weighted mean or
maximum QTc(F) (0-4 h) for any treatment group at any time point. Increases in mean
serial QTc(B) from baseline versus placebo of 6 msec to 12.5 msec within 1 h of dosing
were seen with 50 g GW642444M on all clinic study days, and on Days 1 and 14 with
25 g GW642444M. GW642444M concentration-time data were too limited (high % NQ
values) for formal population PK analysis.
Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
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TheGlaxoSmithKline
GlaxoSmithKline
of companies
The
groupgroup
of companies
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Systemic exposure could only be characterised at doses 12.5 g. Observed Cmax (an
estimate of systemic exposure) increased with dose with marginal increases on repeat
dosing. There was no clear covariate effect on Cmax and no clear correlation between
observed Cmax and any systemic pharmacodynamic endpoint (pulse rate, QTc, glucose
or potassium). At all doses and visits, concentrations of triphenylacetate (counterion)
were below limits of quantification (1 ng/mL) in the majority of subjects. GW642444M
metabolite (GW630200 and GSK932009) concentrations were below limits of
quantification for all doses and visits in the vast majority of subjects (99.8%). Based on a
predicted maximum effect (Emax) model of all the evaluable trough FEV1 data, an ED50
(dose achieving half predicted maximal response) is estimated as 16.1 g [95%CI: 12.519.7 g] and an Emax of 243 mL. The estimated half life of GW642444M was 26 h [95%
CI 23-29 h] in equilibrium with the lung biophase, consistent with a sustained duration of
action. This study demonstrated that, in subjects with moderate to severe persistent
asthma, once-daily treatment with GW642444M was well tolerated and produced a dosedependent and sustained bronchodilatory effect that was superior to placebo at 23-24 h
with the 12.5 g, 25 g and 50 g doses following 28-days treatment.
Subject: Asthma, dose ranging, efficacy, safety, pharmacokinetics, placebo.
Author(s):
29 Dec 2007
Completion Date:
10 Sep 2008
Date of Report:
April 2009
Sponsor Signatory:
(and Medical Officer)
Respiratory MDC
GlaxoSmithKline Research and Development
This study was performed in compliance with Good Clinical Practices and
GlaxoSmithKline Standard Operating Procedures for all processes involved, including
the archiving of essential documents.
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TABLE OF CONTENTS
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Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .
1.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4. STUDY OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1. Discussion of Study Design, Including the Choice of Control
Group(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.2. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . . . . . .
5.4. Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . .
5.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.4. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . .
5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . . . . . . .
5.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . . . . . . .
5.5.3. Medical Device(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.1. Demographic and Baseline assessments . . . . . . . . . . . . . . . . . . . . .
5.6.2. Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.3. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.4. Pharmacokinetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.5. Pharmacogenetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.1. Analyses Supporting the Primary Efficacy Analysis . . . . . . . . . . . . .
7.2. Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.1. Strata Analysis of Trough FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.2. Weighted Mean 24-hour Serial FEV1 . . . . . . . . . . . . . . . . . . . . . . . .
7.2.3. Daily Evening PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.4. Daily Morning PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.5. Symptom-Free 24-hour periods. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.6. Rescue-free 24-hour periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.7. Post-Salbutamol/Albuterol FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Other Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.1. Repeated Measures Analysis of Serial FEV1 . . . . . . . . . . . . . . . . . .
7.3.2. FEV1 (0-4 hours) on Days 1 and 28 . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.3. Symptom-Free Days and Symptom-Free Nights . . . . . . . . . . . . . . . .
7.3.4. Rescue-Free Days and Rescue-Free Nights . . . . . . . . . . . . . . . . . . .
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8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1. Extent of Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1. Adverse Events during the Treatment Period . . . . . . . . . . . . . . . . . .
8.2.2. Post-Treatment Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3. Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Serious Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4. Adverse Events Related to Premature Discontinuation of Investigational
Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5.1. Laboratory Values over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5.2. Abnormalities of Potential Clinical Concern . . . . . . . . . . . . . . . . . . . .
8.6. Other Safety Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.1. Vital signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.2. Twelve-Lead ECG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.3. Potassium and Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.4. Asthma Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.5. Medical Device/Product Incidents, Near-Incidents, Malfunctions
and Remedial Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7. Safety Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9. BIOANALYTICAL RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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13. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
864
864
865
870
Attachment 4. PHARMACOKINETICS/PHARMACODYNAMICS . . . . . . . . . . . . . . .
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LIST OF FIGURES
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LIST OF TABLES
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Abbreviations
AE
ALT
ANCOVA
AM
AST
AV
BD
BDP
BMI
Bpm
CI
COPD
CPK
Cmax
CSR
DMPK
ECG
eCRF
E0
ECG
ED50
eDiary
Emax
FEV1
GCP
GCSP
GINA
GSK
GW642444M
h
HARP
HPLC
IEC
HBsAg
HR
ICH
ICS
IgE
IND
INS
IRB
ITT
L
LABA
Adverse Event
Alanine aminotransferase
Analysis of covariance
Morning (ante meridiem)
Aspartate aminotransferase
Atrioventricular
Bis in die (twice daily)
Beclometasone dipropionate
Body Mass Index
Beats per Minute
Confidence interval
Chronic obstructive pulmonary disease
Creatine phosphokinase
Maximal plasma concentration
Clinical study report
Drug Metabolism and Pharmacokinetics
Electrocardiogram
Electronic case report form
Placebo Effect
Electrocardiogram
Potency; dose producing 50% of maximum predicted
response
Electronic diary
Maximum predicted effect
Forced expiratory volume in 1 second
Good Clinical Practice
Global Clinical Safety and Pharmacovigilance
Global Initiative for Asthma
GlaxoSmithKline
GW642444 formulated with the excipient magnesium
stearate
hour
Harmonisation for analysis and reporting program
High performance liquid chromatography
Independent Ethics Committee
Hepatitis B surface antigen
Heart Rate
International Conference on Harmonisation
Inhaled corticosteroid
Immunoglobulin E
Investigational New Drug
Intranasal corticosteroid
Institutional Review Board
Intent-to-treat
Litre
Long-acting -agonist
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LFT
LLQ
LLR
LOCF
LS Mean
LRT
MAO
MDC
MDI
MedDRA
Min
mL
MS
msec
N
n
NA
NC
ND
NHLBI
NIH
NONMEM
OBJ
OD
PGx
PK
PD
PEF
PGx
PK
PM
PP
PWRES
QC
QTc interval
QTc(B)
QTc(F)
RAMOS
RAP
SA
SAE
SD
SE
SOP
UK
ULN
USA
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WRES
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Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
DISKUS
Inform
MONOLIX
NHANES
NONMEM
OBIWAN
RAMOS
SAS
WinNonlin
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1.
ETHICS
1.1.
The study protocol, any amendments, the informed consent, and other information that
required pre-approval were reviewed and approved by a national, regional, or
investigational centre ethics committee or institutional review board.
1.2.
This study was conducted in accordance with Good Clinical Practice (GCP) and all
applicable regulatory requirements, and the guiding principles of the Declaration of
Helsinki.
1.3.
Written informed consent was obtained from each subject prior to the performance of any
study-specific procedures. Electronic case report forms (eCRFs) were provided for each
subjects data to be recorded.
2.
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4.
STUDY OBJECTIVE(S)
The primary objective of this study was to evaluate the dose response, efficacy and safety
of five doses of GW642444M (3 g, 6.25 g, 12.5 g, 25 g and 50 g) over a 28-day
treatment period in subjects with persistent asthma. The secondary objective was to
characterise the population PK of GW642444 in subjects with persistent asthma.
5.
INVESTIGATIONAL PLAN
5.1.
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The first dose of study medication was given in the clinic at the Visit 2. At the end of the
treatment period there was a 7-day follow-up period. Subjects who completed the study
(screening, Run-in, treatment period and Follow-up) participated in the study for a total
of 7 weeks. Subjects remained on their current ICS therapy (at fixed doses) throughout
the study (screening to follow-up inclusive).
A Time and Events schedule is presented in Table 2.
Figure 1
Clinic Visit 1
Study Day -14
2/2A*
1/2
3
7
4
14
5/5A
28/29
6
(+7)
* Randomisation.
Visit 2/2A and Visit 5/5A took place over 2 days. In selected centres, a proportion of subjects remained in the clinic
overnight (66% of subjects). In other centres, subjects returned to the clinic approximately mid-morning on Day 2 and
Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements.
5.1.1.
This study was designed to build on the experience gained from phase I and phase IIA
studies in healthy subjects and asthma patients and to provide efficacy and safety data in
subjects with persistent asthma.
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A placebo arm was included as suitable reference to establish the magnitude of effect of
GW642444M on efficacy and safety parameters.
Treatment duration of 28 days was considered to be sufficient to demonstrate that the
efficacy of GW642444M is maintained without the development of tolerance.
5.2.
Protocol Amendment(s)
Three protocol amendments were made to the original protocol dated 1 November 2007.
Overall, these amendments were largely for clarification. There was no significant
impact on the patient population before or after any of the amendments, and the
robustness and credibility of the results is unaltered.
Protocol amendment 01 (17 December 2007)
Most of the changes were corrections of inconsistencies within the protocol. The changes
to respiratory tract infections were made in order to allow subjects to enter the trial, with
mild symptoms that did not impact their asthma; this allowed a slightly wider patient
population into the study, but did not make any significant impact on the overall study
population.
The addition of severe milk allergy was made as an addition to lactose sensitivity, in
order to clarify for investigators that subjects with either of these sensitivities should be
excluded. This was a safety warning for a rare allergy, which did not affect the
robustness of the study.
Scope of the amendment:
Clarification that upper and lower respiratory tract infections were only an exclusion
criterion if they resulted in a change to subjects asthma management or if they
affected the subjects ability to participate in the study.
Exclusion criterion 7 was amended to clarify that subjects with severe milk protein
allergy should be excluded from the study1.
Clarification that long-acting anti-histamines only were prohibited for 14 days prior
to and during the study.
It was no longer necessary for Investigators to consult with the GSK Medical
Monitor prior to withdrawing a subject who had met any of the ECG withdrawal
criteria.
No symptoms related to milk protein allergy were identified in any of the subjects.
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Most of the changes were clarifications of the protocol. These included a revision of
some ECG terms, to give greater clarity without changing the original intended exclusion
or withdrawal criteria.
Long-acting anti histamines were allowed because the original protocol allowed short
acting anti-histamines and this was an inconsistency, since multiple doses of a short
acting anti-histamine give a similar effect to a long acting anti-histamine.
Re-screening was introduced with Protocol Amendment 2, but only if the lung function
criteria of FEV1 percent predicted and/or reversibility following inhalation of
albuterol/salbutamol were not met at the original screening visit.
Scope of the amendment:
To allow subjects to re-screen for Visit 1 if they failed to meet lung function criteria
and to allow subjects who previously failed screening to be re-screened.
To clarify the exclusion of subjects with upper and lower respiratory tract infections
between Visit 1 and randomisation Visit 2.
To extend the permitted time deviation windows for serial measurements of lung
function in acknowledgement of the complexity of the study.
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5.3.
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Approximately 1200 subjects were planned to be screened with the aim of achieving
randomisation of 594 evaluable subjects (99 subjects per group) with at least one predose or 23-24 h post-dose FEV1 assessment on or after nominal Day 7.
5.3.1.
Inclusion/Exclusion Criteria
5.3.1.1.
Inclusion Criteria
Subjects eligible for enrolment in the study had to meet all of the following criteria:
1.
Subjects were 12 years of age at Visit 1. In Germany, the Russian Federation and
South Africa, where local regulations or the regulatory status of study medication
permitted enrolment of adults only, subjects recruited were 18 years of age. In
Chile, subjects recruited by one centre were >15 years of age; subjects recruited by
another centre were >18 years of age.
2.
Subjects were male or eligible female. A urine pregnancy test was performed for all
female subjects prior to study participation. To be eligible for entry into the study,
females of childbearing potential had to commit to the consistent and correct use of
an acceptable method of birth control: commit to complete abstinence from
intercourse from screening until 2 weeks after the follow-up contact, sterile sole
partner prior to the subjects entry into the study, implants of levonorgestral,
injectable progestogen, oral contraceptives (combined or progestogen only), double
barrier method, intrauterine or vaginal devices or systems, or percutaneous
contraceptive patches. Female subjects were not enrolled if they were pregnant,
lactating, or planned to become pregnant during the time of study participation.
Females of non-child bearing potential, including females who were postmenopausal, were eligible.
3.
Subjects had a documented history of persistent asthma that was defined by the
National Institute of Health [NIH, 2007]. Their condition had to be first diagnosed at
least 6 months prior to Visit 1.
4.
5.
Subjects had to use an ICS and had to have been maintained on a stable dose for 4
weeks prior to Visit 1.
6.
7.
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8.
9.
In France, subjects were eligible for inclusion in the study only if they were either
affiliated to or a beneficiary of a social security category.
5.3.1.2.
Exclusion Criteria
Subjects meeting any of the following criteria were not enrolled in the study:
1.
2.
3.
4.
Subjects who were hospitalised for an asthma exacerbation within 6 months of Visit
1.
5.
Subjects who had participated in any study using an investigational drug during the
previous 30 days or participated simultaneously in another clinical trial.
6.
Subjects with any clinically significant, uncontrolled condition or disease state that
would put the subjects safety at risk through study participation or would confound
the interpretation of the efficacy results if the condition/disease exacerbated during
the study.
7.
8.
Subjects who were likely to be non-compliant with study medication and other
study-related requirements (e.g. attendance at clinic visits or completion of the daily
eDiary).
9.
10. Subjects who were current smokers or had a smoking history of 10 pack years or
more (e.g., 20 cigarettes/day for 10 years). Subjects were not allowed to have used
tobacco products within the one year prior to the study.
11. Subjects administered systemic, oral or depot corticosteroids or administration of
anti-IgE (e.g. omalizumab [Xolair]) within 12 weeks of Visit 1.
12. Subjects administered any of the asthma medications theophyllines, oral 2-agonists
(e.g. bambuterol), slow-release bronchodilators, short- or long-acting
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Randomisation Criteria
At the end of the run-in period subjects had to fulfil the following additional criteria in
order to enter the treatment period of the study:
1.
Best baseline pre-dose FEV1 at Visit 2 40% and 90% of their predicted normal.
2.
3.
4.
5.
Ventricular rate <45 beats per minute or >90 beats per minute (bpm).
Pathological Q waves, defined as wide (> 0.04 sec) and deep (> 0.4mV [4 mm
with 10 mm/mV setting]) or >25% of the height of the corresponding R wave,
provided the R wave was >0.5mV (5 mm with 10mm/mV setting), appearing in
at least two contiguous leads. Other historical or electrocardiographic evidence
of prior myocardial infarction also excluded the subject.
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Right or left complete bundle branch block, or a QRS interval >120 msec.
Incomplete right bundle branch block (QRS interval >110 msec <120 msec with
right bundle branch block pattern). This was to be confirmed by three readings
at least 5 minutes apart.
6.
7.
8.
9.
10. Compliance with completion of the daily eDiary. Non-compliance with completion
of the Daily eDiary, defined as:
Completion of morning and evening symptom scores on less than 4 days out of
the last 7 days immediately preceding Visit 2.
Completion of morning and evening rescue use on less than 4 days out of the
last 7 days immediately preceding Visit 2.
Completion of morning and evening PEF measurements on less than four out of
the last seven days immediately preceding Visit 2.
5.3.2.
A subject was regarded as having completed the study if they completed all phases of the
study (screening, treatment period and follow-up).
Subjects could be withdrawn from study treatment at anytime by the Investigator if it was
considered to be detrimental for them to continue in the study. Reasons for withdrawal
could include: an AE, lost to follow-up, protocol violation, lack of efficacy, sponsor
terminated study, non-compliance, pregnancy, abnormal liver function test, abnormal
laboratory results, or any other reason. Subjects were also free to withdraw themselves at
anytime. Once withdrawn from the investigational product a subject was considered
withdrawn from the study.
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An increase in heart rate from baseline of >40 bpm (relative to the pre-dose Day
1 value) or an absolute heart rate of >110 bpm during the treatment period. This
was to be confirmed by 3 readings at least 5 minutes apart.
Ventricular rate <37 bpm. This was confirmed by 3 readings at least 5 minutes
apart on 3 or more ECGs.
Pathological Q waves, defined as wide [> 0.04 seconds] and deep (> 0.4mV [4
mm with 10mm/mV setting]) or > 25% of the height of the corresponding R
wave, provided the R wave was >0.5 mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads. Subjects were also to be withdrawn
in case of historical or electrocardiographic evidence of prior myocardial
infarction.
Right or left complete bundle branch block, or a QRS interval >120 msec.
Incomplete right bundle branch block (QRS interval >110 msec <120 msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.
2.
a.
Clinic FEV1 below the FEV1 Stability Limit value calculated at Visit 2 pre-dose
FEV1 at Visit 2 x 80%.
b.
During the 7 days immediately preceding the visit, the subject experienced any of the
following:
More than 3 days in which PEF had fallen below the morning PEF Stability
Limit calculated at Visit 2 (Mean morning PEF from the 7 days preceding Visit
2 x 80%).
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ALT 5 x ULN.
5.4.
Investigational Product(s)
5.4.1.
GSK Clinical Trials Supplies, Ware, UK manufactured and supplied the study medication
as detailed in Table 1. GW642444M and placebo were administered via Novel Dry
Powder Inhalers each containing two foil blister strips.
Table 1
Compound
Formulation
GW642444M
First strip: GW642444X micronised drug (as the M salt
triphenylacetate) blended with lactose and magnesium stearate.
Second strip: placebo containing lactose.
Novel Dry Powder Inhaler 30 doses per device
Dosage Form
Unit Dose
Strength(s)
a.
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Placebo
First strip: blend of lactose
and magnesium stearate.
Second strip: lactose.
Novel Dry Powder Inhaler 30
doses per device
Batch
and
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All study medications were stored in a secure area under appropriate physical conditions.
The Novel Dry Powder Inhalers containing GW642444M or matching placebo were
stored between 2 and 8C prior to being dispensed to subjects. Following dispensing, the
study medication was stored below 25C.
Subjects were provided with salbutamol/albuterol MDIs for use as rescue medication
throughout the study. The MDIs were sourced locally or by GSK for sites in the USA
and Canada.
5.4.2.
At Visit 2, subjects were randomised in equal numbers to one of the following dosing
regimens:
Placebo (1 actuation) administered once-daily via the Novel Dry Powder Inhaler in
the evening.
At Visits 2/2A, 3, 4 and 5, subjects were required to take their dose of study medication
at the clinic. At Visits 3, 4, and 5, treatment was administered at approximately the same
time of day ( 1 h) as Day 1 (Visit 2). On the other days, subjects were instructed to take
their study medication within 1 h of their dose time on Day 1 (Visit 2).
5.4.3.
Dose Rationale
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Blinding
This was a double-blind study. Neither the subject nor the investigator knew which study
medication the subject was receiving. The placebo dry powder formulation was
indistinguishable from the GW642444M formulation.
The investigator or treating physician was able to unblind a subjects treatment
assignment only in the case of an emergency, when knowledge of the study treatment
was essential for the appropriate clinical management or welfare of the subject.
Furthermore, GSKs Global Clinical Safety and Pharmacovigilance (GCSP) staff could
unblind the treatment assignment for any subject with an SAE. Further details can be
found in the Protocol.
5.4.5.
Treatment Assignment
The central randomisation schedule was generated by GSK using RandAll, a web serverbased, clinical trials randomisation system. Subjects were randomised centrally using
Registration and Medication Ordering System (RAMOS), an automated, interactive
telephone based system which was used by the Investigator or designee to register the
subject, randomise the subject and receive medication assignment information. Prior to
randomisation, subjects were stratified by baseline FEV1 as a percentage of predicted
(FEV1 40% - 65% predicted and FEV1 > 65% - 90% predicted) in an approximately
1:1 ratio. Within each stratum, allocation was centralised, with a block size of 6.
5.4.6.
Assessment of Compliance
Subjects were required to take their study medication every evening of each day during
the treatment period. At clinic Visits 2/2A, 3, 4 and 5 study drug administration was
observed by appropriately trained site personnel. Compliance throughout the study was
assessed at Visits 2 through 5 by reviewing the dose counter on the Novel Dry Powder
Inhaler. Percentage treatment compliance was calculated for each subject based on the
total number of inhalations taken and the expected number of inhalations to be taken.
Subjects who were not compliant with study drug administration were counselled on
appropriate dosing of the study drug.
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GSK did not recommend specific treatment guidelines for overdose and toxicity
management relating to GW642444M. The investigator was asked to refer to the relevant
documents for detailed information regarding warnings, precautions, contraindications,
AEs, and other significant data pertaining to the study drug being used in this study, such
documents as the Investigators Brochure and to use clinical judgment in treating the
overdose.
5.5.
All concomitant medications taken during the study were recorded in the eCRF.
5.5.1.
Permitted Medications
ICSs, provided the dose remained constant for 4 weeks prior to Visit 1 and
throughout the study.
Medications for other disorders (other than those listed in Section 5.5.2) were permitted
provided the dose remained constant and their use would not be expected to affect the
subject's lung function. Subjects were allowed to use non-drug therapies for conditions
other than asthma during the study if their use was not considered likely to have an
impact on the subject's asthma.
If a subjects current medication was changed as a result of study participation, then
consent was obtained at this point and the subject was required to return to the clinic to
complete the screening visit (Visit 1) once the required washout had been completed.
5.5.2.
The following medications were not permitted during the study or within the specified
time prior to the study.
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Long-acting 2-agonists.
Theophyllines.
Oral 2 agonists.
Slow-release bronchodilators.
Anti-IgE therapy.
In addition, a subject was not concurrently allowed to use any other prescription or overthe-counter medication which could affect the course of asthma, or interact with
sympathomimetic amines throughout the study (Visit 1 to Visit 6 inclusive), such as:
Anticonvulsants.
Polycyclic antidepressants.
Phenothiazines.
MAO inhibitors.
5.5.3.
Medical Device(s)
GSK provided the eDiary device with integrated peak flow meter (Asthma Monitor
AM2+, Cardinal Health Research Services).
5.6.
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Table 2
Procedures
Visit
Day
Written Informed
Consent
Subject Demography
x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination
x
Inclusion/Exclusion
x
Criteria
Randomisation Criteria
Efficacy Assessments
Clinic measured FEV1
x
FEV1 response to
x12
salbutamol/albuterol
x
Issue eDiary with
integral PEF meter9
Review eDiary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
Serum Pregnancy Test x
Treatment
2/2A1
1
Early
withdrawal
3
7(-4/+2)
4
14(-4/+2)
5/5A1
28(-4/+2)
Follow-up
6
D28+7(-4/+2)
x
x2
x3
x2
x2
x2
x3
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
13
x5
x
x7
x10
x
x11
x
x11
x
x7
Continued
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Table 2
Procedures
Visit
Day
Investigational product
Dispense Invest.
Product.
Assess Invest. Product
compliance
Collect invest. product
Issue rescue
x
salbutamol/albuterol
Collect used rescue
salbutamol/albuterol
Treatment
2/2A1
1
Early
withdrawal
3
7(-4/+2)
4
14(-4/+2)
5/5A1
28(-4/+2)
Follow-up
6
D28+7 (-4/+2)
x8
x8
1.
Visit 2/2A and Visit 5/5A took place over 2 days. In selected centres, a proportion of subjects remained in the
clinic overnight (66% of subjects). In other centres, subjects returned to the clinic approximately mid-morning on
Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements.
2.
On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 were made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 h post-dose. Measurements at 6 and 12 h post-dose were
only made in those subjects remaining at the clinic overnight. On Days 7 (Visit 3) and 14 (Visit 4) pre-dose FEV1
measurements were required only.
3.
Performed 24 h after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of the investigational product.
4.
Measurements were made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose, 10
minutes and 1, 2 and 4 h post-dose.
5.
6.
7.
Samples were taken pre-dose and 10 minutes, 1, 2 and 4 h post-dose. Subject was fasted from at least 4 h prior
to the pre-dose blood sample until after the 4 h post-dose sample.
8.
If required.
9.
Morning and evening PEF, symptoms and rescue medication usage was recorded every day from Visit 1 through
Visit 6.
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Where multiple post-dose assessments were scheduled at the same timepoint, the
sequence of assessments was to be vital signs followed by 12-lead ECG, blood sampling
and FEV1 measurements. FEV1 measurements were performed as close to the scheduled
timepoint as possible.
5.6.1.
The information described in this section refers to the assessments made at Screening
(Visit 1).
At Screening, the following information was obtained: height and weight, gender, ethnic
origin, date of birth, asthma history (including duration of asthma and atopic status),
smoking history, severity of disease, reversibility to salbutamol/albuterol and concurrent
medical conditions. Subjects also underwent a physical examination, vital signs
assessment (heart rate, blood pressure), 12-lead ECG assessment, pre-dose blood
sampling for haematology, clinical chemistry, urinalysis, serum pregnancy test (all
female subjects), and HBsAg and hepatitis C antibody tests. All demographic and
baseline assessments were completed according to the Time and Events schedule
(Table 2).
Subjects who had at least one study procedure performed (in addition to signing a consent
form) and who were assigned a study number, but who were not randomised were
considered screen failures.
Subjects who had previously screen-failed for any reason prior to Protocol Amendment
02 were allowed to return to the site for re-screening. Subjects who failed to meet the
FEV1 and/or reversibility inclusion criteria during Screening Visit 1 were allowed to
return once within 4 days to repeat the lung function tests.
5.6.2.
Efficacy Assessments
The primary efficacy endpoint was the mean change from baseline in clinic visit trough
(pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period. The
trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 h after
dosing on Day 28.
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Change from baseline in weighted mean 24 h serial FEV1 on Days 1 and 28 (mean
post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24
h). This endpoint was derived for all subjects but the 6 and 12 h time points were
only measured in a sub-group of subjects (66% of subjects).
Mean change from baseline in daily morning PEF averaged over the 28-day
treatment period.
Mean change from baseline in the percentage of symptom-free 24-h periods during
the 28-day treatment period.
Mean change from baseline in the percentage of rescue-free 24-h periods during the
28-day treatment period.
5.6.2.3.
Proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
(0-4 h) on Days 1 and 28.
Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24 h,
7 and 14 days of treatment).
Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.
Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.
Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.
Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.
Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.
Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.
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5.6.2.4.
Exploratory endpoints, not specified in the protocol, but that were specified in the
Reporting and Analysis Plan (RAP), included:
Weighted mean change from baseline (0-4 h) for FEV1 on Days 1 and 28.
Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 was defined as the
mean of the FEV1 values obtained 23 and 24 hours (h) after dosing on Day 28, with
no imputation.
5.6.2.5.
Assessments
FEV1 was measured electronically at all clinic visits in the evening prior to study
medication dosing. Subjects were instructed not to use their rescue albuterol/salbutamol
for at least 6 h prior to the clinic visit. The highest of three technically acceptable
measurements was recorded. At Visit 1 (Screening), FEV1 was measured between 5PM
and 10PM; at Visit 2, pre-dose FEV1 was obtained between 5PM and 8PM. At each
subsequent visit, pre-dose FEV1 was obtained within 1 h of the time of the measurement
of the pre-dose FEV1 at Visit 2. At Visits 3 and 4, FEV1 was measured 23-24 h after the
last dose of study medication.
At Visit 1 (Screening), subjects eligibility was determined by assessing FEV1
reversibility immediately before and 30 minutes after administration of 400 g
salbutamol/albuterol via MDI or 1 nebulised salbutamol/albuterol solution. Subjects who
failed to demonstrate a 12% and 200 mL increase in FEV1 at this visit were not
eligible to take part in the study; however, subjects were allowed to return once within 4
days to repeat this test. If the subject met the lung function entry criteria on the second
attempt, then other Visit 1 procedures were to be performed on this Visit. At Visit 2, the
best pre-dose FEV1 had to be 40% and 90% of the subjects predicted normal to ensure
eligibility.
For randomised subjects an FEV1 Stability Limit was determined, which was derived
from the best pre-dose FEV1 at Visit 2.
In addition to the pre-dose FEV1 measurements at Visits 2 and 5, serial 24-h FEV1
measurements were taken post-dose (see Table 2). At each time point, the highest of a
minimum of three technically acceptable measurements was recorded.
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Response to salbutamol/albuterol
Following completion of the serial 24-h FEV1 measurements at Visit 2 and Visit 5, post
salbutamol/albuterol FEV1 was measured. The subject was administered a single 400 g
dose of inhaled salbutamol/albuterol via MDI or 1 dose of nebulised salbutamol/albuterol
solution and FEV1 was measured 30 minutes after this administration. The highest of
three technically acceptable measurements was recorded. These assessments were
performed as follows:
6 h after the last use of salbutamol/albuterol (compliance with this was recorded in
the spirometry equipment).
24 h after the first dose (Visit 2) or last dose (Visit 5) of study medication.
For Visit 2/2A only, before the dose of study medication was taken on treatment Day
2.
Diary parameters
Daily eDiary parameters were recorded in the electronic daily eDiary from Run-in to
Follow-up. These included morning and evening PEF, day-time and night-time asthma
symptom scores, number of inhalations of rescue salbutamol/albuterol usage during the
day and night, and whether they had taken their regular ICS medication. Subjects
returned their eDiaries to the investigator at each clinic visit. At Visit 2, the eDiary was
checked against the randomisation criteria. At Visits 3, 4 and 5 the Investigator reviewed
all eDiary data to confirm that the Subjects had not met the criteria for withdrawal due to
lack of efficacy.
Subjects were issued a paper medical conditions diary to record adverse events during the
study (see Section 5.6.3). On the paper diary subjects were asked to record the time of
dosing of their study medication on the day (evening) before the clinic visit.
Peak Expiratory Flow Measurements
Morning and evening PEF were measured each morning prior to any rescue
salbutamol/albuterol use and each evening prior to study medication dose (and if
possible, rescue salbutamol/albuterol use) using the eDiary which had a built-in peak
flow meter issued to subjects at Visit 1. Three PEF measurements were made within 30
minutes of each other for each PEF time point and the highest PEF value was recorded in
the daily eDiary. For randomised subjects, a PEF Stability Limit (derived from mean
morning PEF from the available 7 days preceding Visit 2) was calculated by the daily
eDiary.
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Asthma Symptom Scores were recorded BD in the daily eDiary prior to taking any rescue
salbutamol/albuterol or study medication (evening only), and prior to making any PEF
measurements. These reflected the symptoms for the previous day and night and used the
following scales:
Day-time Symptom Score (recorded each evening):
0.
1.
2.
3.
Symptoms for most of the day which did not affect my normal daily activities.
4.
Symptoms for most of the day which did affect my normal daily activities.
5.
Symptoms so severe that I could not go to work or perform normal daily activities.
1.
2.
3.
4.
Each morning and evening, subjects recorded in their daily eDiary the number of rescue
salbutamol/albuterol inhalations taken using the issued MDIs during the previous 12 h.
Use of spacer devices was not permitted.
Withdrawals Due to Lack of Efficacy
Safety Assessments
During the study, safety was assessed by monitoring AEs and SAEs, clinical laboratory
tests (haematology, chemistry and urinalysis), vital signs (pulse rate and systolic and
diastolic blood pressure), 12-lead ECGs, and potassium and glucose levels. The
measurements are outlined in Table 2.
From the time a subject consented to participate in and completed the study (including
any follow-up period), all SAEs assessed as related to study participation (e.g., protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK
concomitant medication, were reported promptly to GSK. The time period for collection
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Adverse Events
An SAE was defined as any untoward medical occurrence that, at any dose:
1.
Resulted in death;
2.
Was life-threatening;
3.
4.
Resulted in disability/incapacity; or
5.
6.
5.6.3.3.
Asthma exacerbations
For the purposes of this study, a subject was withdrawn due to lack of efficacy if they
experienced a clinical exacerbation, or at the investigators discretion. An exacerbation
was defined as worsening asthma requiring any treatment other than study medication or
rescue salbutamol/albuterol or the subjects regular ICS use. This included requiring the
use of systemic corticosteroids and/or emergency room visit or hospitalisation or a
change in inhaled corticosteroid dose.
Asthma exacerbations were not to be recorded as an AE, unless they met the definition of
an SAE (See Section 5.6.3.2). For the purposes of this study, asthma exacerbations were
recorded on the exacerbations log in the eCRF. The time period for collection of asthma
exacerbations began from the time of randomisation (first receipt of investigational
product) and ended after the Follow-up period had been completed.
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Pregnancies
Haematology and clinical chemistry tests were performed after 14 days and 28 days of
treatment and dipstick urinalysis parameters after 28 days of treatment (Table 2). All
blood samples were sent to a central laboratory for analysis. A mid-stream urine sample
was collected for urinalysis tests. These were analysed in a central laboratory.
If the clinical laboratory tests were taken prior to performing the lung function testing and
the subject met the lung function entry criteria based on the second lung function attempt
(within 4 days of Visit 1), the investigator was to document that the laboratory results
were clinically acceptable within the 4-day screening period. Additional samples could
be taken for safety reasons at the discretion of the investigator.
Fasting serum potassium and plasma glucose were monitored to assess the PD effects of
GW642444M. Subjects were asked to fast for at least 4 h prior to the planned blood draw
at Screening (Visit 1) and for at least 4 h prior to the pre-dose blood samples and until
after the 4 h post-dose blood samples at Visits 2 and 5. Non-fasting potassium was
monitored at Visits 3 and 4. The following endpoints were derived:
Maximum decrease from baseline and from pre-dose (0-4 h) for potassium.
Weighted mean change from baseline and from pre-dose (0-4 h) for potassium.
Maximum increase from baseline and from pre-dose (0-4 h) for glucose.
Weighted mean change from baseline and from pre-dose (0-4 h) for glucose.
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12-Lead ECGs
12-lead ECGs were measured by the investigator or his/her suitably qualified designee at
Visits 2, 3, 4 and 5 (Table 1) to derive the following endpoints:
Weighted mean change from baseline and from pre-dose (0-4 h) in QTc(F) (QT
interval corrected by Fridericia's method).
Weighted mean change from baseline and from pre-dose (0-4 h) in QTc(B). (QT
interval corrected by Bazett's method).
ECGs were recorded after 5 minutes rest, after measurement of vital signs and before
clinic lung function tests at the specified time. If the subject failed the lung function
criteria at the first attempt, and only became eligible for the study at the second screening
visit the investigator was to document that the ECG results were clinically acceptable
within the 4-day screening period.
A cardiologist who was independent from GSK and who was blinded to treatment
assignment was responsible for providing an official interpretation of all ECGs collected.
A hard copy of the results was sent to the study site. If there was a discrepancy between
the assessment by the investigator and that by the independent cardiologist, the
assessment of the latter was used in all analyses and data presentations.
At Visit 2, the manual reading and calculation of the ECG parameters was used to
determine whether a subject met the eligibility criteria for enrolment in the study. Also at
this visit, the pre-dose ECGs were interpreted by the independent cardiologist as: within
normal limits; abnormal, not clinically significant; or abnormal, clinically significant. If
the pre-dose ECG at Visit 2 was judged to be abnormal and clinically significant, the
subject was to be withdrawn from the study. If any of the abnormalities in ECGs
outlined in Section 5.3.2 (withdrawal criteria) were observed pre-dose Visit 2 or after
randomisation, the subject was withdrawn from treatment.
The ECG was repeated at the Follow-up visit if it was clinically significantly abnormal at
Visit 5.
Vital signs
At Visits 2, 3, 4 and 5, pulse rate and systolic and diastolic blood pressure measurements
were performed in the sitting position after 5 minutes rest. Measurements were taken
before any clinic lung function assessments or ECGs at the specified time point. The
following endpoints were derived:
Change from baseline and from pre-dose in maximum value (0 - 4 h) for systolic
blood pressure.
Change from baseline and from pre-dose in minimum value (0 - 4 h) for diastolic
blood pressure.
Change from baseline and from pre-dose in maximum value (0 - 4 h) for pulse rate.
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Weighted mean change from baseline and from pre-dose (0 - 4 h) for blood pressure
and pulse rate.
Pharmacokinetic Assessments
Assessments
Visits 2 and 5: subjects attended the evening clinic without having taken their study
medication. A pre-dose sample was collected at the beginning of their clinic visit.
Additional samples were then taken post-dose. Every attempt was made to collect
samples at times spread throughout the time window.
Visit 3: subjects attended the evening clinic without having taken their study
medication. A pre-dose sample was collected at the beginning of their clinic visit.
Visit 4: Subjects attended the evening clinic without having taken their study
medication. One sample was taken post-dose. Every attempt was made to collect
samples at times spread throughout the time window.
Only samples from subjects receiving GW642444 were analysed for GW642444,
GI179710, GW630200 and GSK932009. In a change from what is stated in the protocol,
samples from subjects on all dose levels of GW642444 were analysed for the metabolites
(GW630200 and GSK932009) and the triphenylacetate counterion.
PK Sample Assay: Human plasma samples were analysed for GW642444, GSK932009,
GW630200 and GI179710 using a validated analytical method based on protein
precipitation, followed by high performance liquid chromatography/mass
spectrometry/mass spectrometry (HPLC/MS/MS) analysis. Two methods were used, the
first method has a lower limit of quantification (LLQ) of 30 pg/mL for GW642444, 180
pg/mL for GSK932009 and 90 pg/mL for GW630200 using a 150 L aliquot of human
plasma [GlaxoSmithKline Document number: WD2006/02197/00, 2006]. The second
method has a LLQ of 1 ng/mL for GI179710 using a 100 L aliquot of human plasma
[GlaxoSmithKline Document number: WD2006/02527/00, 2006]. The computer systems
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that were used on this study to acquire and quantify data included Analyst Version 1.4.1
and 1.4.2 and SMS2000 version 2.0 and 2.1
Methods for the determination of GW642444, GSK932009, GW630200 and GI179710 in
human plasma (range 30 to 15000, 90 to 45000, 180 to 90000 pg/mL and 1 to 1000
ng/mL, respectively) using HPLC/MS/MS have been validated. Within-run precision and
accuracy of quantification during the validation for GW642444, GSK932009,
GW630200 and GI179710 was better than 15% across the concentration range.
Quality Control (QC) samples, prepared at three different analyte concentrations and
stored with study samples, were analysed with each batch of samples against separately
prepared calibration standards. For the analysis to be acceptable, no more than one-third
of the QC results were to deviate from the nominal concentration by more than 15%, and
at least 50% of the results from each QC concentration should be within 15% of nominal.
All applicable analytical runs met all predefined run acceptance criteria.
In total, 504 subjects provided 5564 PK samples (non-missing) following administration
of GW642444M (3 - 50 g).
5.6.5.
Pharmacogenetic Assessments
Written approval from the IEC/IRB and, where required, the applicable regulatory
agency was required before PGx assessments could be conducted at the site. If approval
of PGx assessments occurred after approval was obtained for the rest of the study, the
written approval was to clearly indicate that approval of the PGx assessments was being
deferred and that the study, except for PGx assessments, could be initiated. When PGx
assessments were not approved, then the approval for the rest of the study clearly
indicated this and therefore, PGx assessments were not conducted.
Subjects who consented to participate in the PGx research provided a blood sample at
Visit 2.
5.7.
In accordance with applicable regulations, GCP and GSK procedures, GSK monitors
contacted the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical and GSK
requirements. GSK monitored the study to ensure that the data were authentic, accurate
and complete; safety and rights of subjects were being protected; and that the study was
conducted in accordance with the currently approved protocol and any other study
agreements, GCP and all applicable regulatory requirements. GSK could conduct a
quality assurance audit of the site records and the regulatory agencies could conduct a
regulatory inspection at any time during or after completion of the study.
Subject data were captured and completed within 7 days of the subject visit by the
investigator or his/her designee using an eCRF. This study used the InForm eCRF (Phase
Forward, UK), which is a web-based clinical trials data management system. Activities
performed using InForm include data entry, modification, review and validation of
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clinical data. Each activity performed carries a unique user identification code and a
date-time stamp. Study-specific training on eCRF completion was provided at the
monitors and investigator meetings. Additionally, an InForm interactive training
database was available to site staff and study monitors for independent follow-up
training.
The eCRF was fully validated using test data, prior to distributing the url for site use.
Encrypted clinical trial data were transmitted from the site via the internet to a firewallprotected network server, and then via an application server into the clinical database.
An electronic audit trail of all changes made to the eCRF was kept within the InForm
system. This audit trail identified the user making the change by user ID, and date and
time of change. Pre-defined data validation checks were run within the eCRF as the data
were entered and submitted by authorized site staff. The resulting data queries were then
resolved. Additional queries were generated within the eCRF by authorized GSK staff
following data review. All data queries issued were to be answered by the site within 7
days from the date of issue or sooner as the study came to an end or, for example if GCSP
required a quick turnaround on SAEs information or data queries were required for
regulatory reports.
The principal investigator electronically signed and dated each InForm casebook attesting
to his/her responsibility for the quality of all data included therein, and that the data
represented a complete and accurate record of each subject's participation in the study.
At the end of the study, once all data queries were resolved, a CD-ROM containing eCRF
PDFs (the PDF contained all of the patient's eCRF data, the data queries, and a copy of
the audit trail) was sent to site along with a letter explaining how to view the data on the
PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt of the CD.
After data management procedures were completed, the database was released on 20
October 2008. Following release the database was frozen on 22 October 2008. The
original validated data (eCRFs, etc.) were archived according to company standard
procedures.
Subjects were also provided with a paper medical conditions diary card on which they
recorded all medical problems which may have occurred and all medications (except
study-related medications) taken to treat medical problems, as well as the time of
previous days dose (for PK assessments). Sites were instructed to review the paper diary
card and record all medical problems, which were considered AEs, and record all
concomitant medications into the eCRF at every study visit. Once completed, sites were
required to tear out the diary card page from the previous period at each visit and store in
the patient notes.
Diary data were collected using Asthma Monitor 2+ (AM2+, Cardinal Health Services)
eDiary every day throughout the study from Visit 1 (Screening) to Visit 6 (Follow Up)
and downloaded to the Cardinal Health Research Services server at the clinic visits. The
Cardinal Health Research Services Masterscope CT Users manual had primary contact
information for subject help requests.
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GSK Data Management and Cardinal Health Research Services performed limited data
checking, comparing the eDiary visit information to the eCRF visit information to ensure
consistency across each subject's data. Any data queries that arose (e.g., if a visit had
occurred in InForm eCRF but there was no corresponding data from Cardinal Health
Research Services) was either sent directly from the vendor or generated in the InForm
system, and had the same turnaround timelines as those for other InForm data. All
queries had to be addressed and closed prior to releasing the database.
In addition to InForm eCRF data, electronic laboratory data (Quest Laboratories, UK),
electronic spirometry data, ECG and electronic diary data (Cardinal Health Research
Services) were delivered to GSK. These data were reconciled with the eCRF data and
any resulting discrepancies were queried either within the eCRF or by the vendor using
their own SOPs. All queries had to be addressed and closed prior to releasing the
database.
Quality Control (QC) tasks were conducted in accordance with existing data management
standard operating procedures to ensure database accuracy against the data collected in
the eCRF and any other subject-completed documents. QC procedures are in alignment
with the International Conference on Harmonisation of Good Clinical Practice (ICH
GCP).
AEs and concomitant medications terms were coded using the Medical Dictionary for
Regulatory Activities (MedDRA) and GSKDrug, an internal validated medication
dictionary. An appropriate medical dictionary that covered all approved drugs in the
region was referenced.
SAE data were documented according using the SAE data collection tool. Once an
investigator became aware that an SAE has occurred in a study subject, he/she was to
report the information to GSK within 24 h, as outlined in the Protocol.
5.8.
Further details are provided in the Reporting and Analysis Plan (RAP).
5.8.1.
All planned analyses were performed after the database freeze had taken place. No
interim analysis was planned or conducted.
5.8.1.1.
The following changes in analyses were made after RAP sign-off but before unblinding2:
These changes were documented in filenotes to the study file before unblinding.
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Addition of a box plot of the maximum increase from baseline in pulse rate.
The first two rules stated in Section 10.2 of the RAP for protocol deviations3 were
changed as follows:
Inclusion criteria 3, 4, 5, 6, 8.
Post-Hoc Analyses
Summary of the proportion of subjects obtaining 200mL and 12% increase from
baseline FEV1 (0-24 h) (Table 7.105 and Figure 7.109).
Potassium profiles for subjects with values >7 mmol/L (Figure 8.101).
5.8.2.
The sample size of 594 subjects (99 subjects per group) with at least one pre-dose or 2324 h post-dose FEV1 assessment on or after nominal Day 7 was based on the primary
endpoint of change from baseline in trough FEV1. This approach had 97% power to
detect a slope of 4 mL/g (a dose response effect of 200 mL improvement in FEV1 per 50
g of GW642444M), assuming a standard deviation of 430 mL based on previous studies
and significance declared at the two-sided 5% level.
Similarly, there was >99% power to detect slopes of 8 mL/g (200 mL improvement per
25 g dose), 16 mL/ g (200 ml improvement per 12.5 g dose) and 32 mL/g (200 mL
Subjects with protocol deviations were defined as those who were randomised or entered into the trial, but
deviated from the protocol. Protocol deviations could be either full or partial (see Section 10.2 of the
RAP).
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improvement per 6.25 g dose). The 3 g dose was assumed to be a non-effective dose
and the study had approximately 96% power to detect a 200 mL effect between this dose
and the 50 g dose, excluding placebo from the dose-response analysis. Furthermore, the
study had 90% power to detect a difference of 200 mL in pair-wise comparisons of
change from baseline in trough FEV1 between any active dose and placebo. Pair-wise
tests of each dose versus placebo were only performed if the linear trend in dose-response
proved significant.
Any subject whose FEV1 measurement at Day 28 was missing was included in the
analysis of the primary endpoint by imputation using the preceding non-missing trough
FEV1 value (Last Observation Carried Forward [LOCF]). Trough values prior to Day 7
pre-dose were not carried forward. Similarly, the primary endpoint was also analysed
using Repeated Measures whereby missing data were not directly imputed but the
correlation between visits for all subjects was used to adjust the estimate of treatment
effect.
No sample size review was planned or was conducted for this study.
5.8.3.
Analysis Populations
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Treatment Comparisons
The primary treatment comparison was a test of linear trend in dose response in trough
(pre-bronchodilator and pre-dose) evening FEV1 derived from the mean of the 23 and 24
h post-dose assessments at Day 28 across the five doses of GW642444M and placebo in
order to demonstrate overall efficacy of GW642444M relative to placebo. If the test of
linear trend was statistically significant, pair-wise tests of each dose versus placebo were
to be performed to identify effective doses. These comparisons were performed using the
ITT Population using Analysis of Covariance (ANCOVA) with LOCF to impute missing
data. A supporting analysis was also performed using a Repeated Measures Mixed
Model. Missing data were not implicitly imputed in this analysis. However, all nonmissing data for a subject were used within the analysis to estimate the Day 28 treatment
effects.
Since the pair-wise comparisons with placebo were only to be performed if the trend test
demonstrated overall efficacy of GW642444M, no further multiplicity adjustments were
planned.
The primary comparisons were supported by the same tests performed using the PP
Population. Furthermore, the dose response across the five doses of GW642444M was
explored using the ITT Population excluding placebo from the analysis.
Pair-wise comparisons were performed for all of the secondary and other efficacy
endpoints.
5.8.5.
All programming was performed in a Harmonisation for Analysis and Reporting Program
(HARP) environment using SAS Version 8.2 or a later release.
5.8.5.1.
Multicentre studies
This study was conducted in 88 centres (worldwide). All centres within the same country
were pooled. Countries enrolling less than 12 subjects in total were pooled with other
countries within a similar geographical region and these amalgamations were used
whenever country was included in the analysis. All summaries and analyses were of all
countries combined (analysis models included country as a covariate).
5.8.5.2.
All models used for the efficacy and safety analyses were adjusted for baseline value,
country, sex, age, baseline percent predicted FEV1 stratum and treatment group. Any
stratum by treatment interaction was explored as part of the model-checking process.
5.8.5.3.
Examination of subgroups
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Multiple comparison/multiplicity
No multiplicity adjustments were applied, for the reasons stated in Section 5.8.4.
5.8.6.
Study Population
Efficacy Analyses
The primary endpoint of mean change from baseline at Day 28 in trough (evening prebronchodilator and pre-dose) FEV1 was derived from the mean of the 23 and 24 h postdose assessments. The dose-response was evaluated for Day 28. Provided the doseresponse test was statistically significant, estimated treatment differences for all pair-wise
comparisons for Day 28 were presented. These primary analyses were performed using
ANCOVA models on the Day 28 data with effects due to baseline FEV1, centre grouping
(country), age, sex, baseline percent predicted FEV1 stratum and dose/treatment group,
imputing missing data using last observation carried forward (LOCF).
The primary analyses were also performed on the PP Population.
The primary comparisons were also performed in a sensitivity analysis using a repeated
measures model allowing for effects due to baseline FEV1, centre grouping, age, sex,
baseline percent predicted FEV1 stratum, visit and treatment group. Data from Day 7
(pre-dose assessment), Day 14 (pre-dose assessment), and Day 28 (pre-dose assessment
and the mean of the 23 and 24 h post-dose assessments) were included. This model also
contained a visit-by-treatment interaction term. A linear trend contrast was constructed
for Day 28 to evaluate the dose-response trend.
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The primary endpoint of change from baseline in trough FEV1 at the end of treatment
was analysed for each percent predicted FEV1 strata separately, in order to investigate the
consistency of the dose-response relationship for the different disease severities. An
ANCOVA model with effects due to baseline trough FEV1, centre grouping, age, sex and
dose was used to estimate the dose response slope for each baseline percent predicted
FEV1 stratum. An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, stratum, treatment group and treatment group-by-stratum interaction
was used to estimate the treatment differences for all pair wise comparisons for each
stratum. Statistical significance testing was not performed for the strata analyses.
Summaries of the as-randomised and actual stratum, and summaries by actual stratum of
Day 1 pre-dose percent predicted FEV1 were presented.
0-24 h Weighted mean serial FEV1
The 24-h serial FEV1 was measured on Days 1 and 28 (pre-dose, and 15, 30 and 60
minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 h post-dose), with the 6 and 12 h time
points only measured in a subgroup of subjects. The change from baseline in weighted
mean for 24-h serial FEV1 on Days 1 and 28 was compared using an ANCOVA model
for each GW642444M group versus placebo.
Additionally, three sensitivity analyses were performed to assess the impact of the 6-12
hour time points, as follows:
Subset of subjects who had the 6-12 h time points measured. All time points were
included.
Subset of subjects who had the 6-12 h time points measured. The 6-12 h time points
were excluded.
For PEF-related endpoints, the baseline value was derived from the last 7 days of the
daily eDiary prior to the randomisation of the subject.
Evening trough PEF
The change from baseline in daily trough (pre-dose and pre-rescue bronchodilator)
evening PEF averaged over the 28-day treatment period was compared using an
ANCOVA model for each GW642444M dose versus placebo.
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Morning PEF
The change from baseline in daily morning PEF averaged over the 28-day treatment
period was compared using an ANCOVA model for each GW642444M dose versus
placebo.
Percentage of symptom- and rescue-free 24-h periods
The change from baseline in the percentage of symptom-free 24-h periods and rescuefree 24-h periods over the 28-day treatment period was calculated for each subject.
Baseline was derived from the last 7 days of the daily eDiary prior to randomisation of
the subject. Comparisons were then made using an ANCOVA model of each
GW642444M dose versus placebo.
Response to salbutamol/albuterol
Baseline in this analysis was defined as the pre-salbutamol FEV1 value taken at
Screening Visit 1.
5.8.8.3.
Details of other efficacy measures are provided in Section 11.3 of the RAP.
FEV1 (0-4 h) on Days 1 and 28
The maximum increase and weighted mean change in FEV1 (0-4 h) on Days 1 and 28
compared with baseline was calculated for each subject. Comparisons were then made of
each GW642444M dose versus placebo using an ANCOVA model with effects due to
baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment group. Estimated treatment differences for all comparisons were presented.
Summaries were produced for the proportion and cumulative proportion of subjects
obtaining both 200 mL and 12% increase from baseline in FEV1 (0-4 h) at each
planned time point on Days 1 and 28; the proportion and cumulative proportion of
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subjects obtaining 15% increase from baseline in FEV1 (0-4 h) at each planned time
point on Days 1 and 28; and peak to trough FEV1 ratio on Day 28. Peak post-dose FEV1
(0-4 h) on Day 28 was also summarised and analysed as described above for maximum
increase in FEV1 (0-4 h).
Percentage of Symptom-free and Rescue-free Days and Nights
The mean change from baseline in the percentage of symptom-free days, symptom-free
nights, rescue-free days and rescue-free nights over the 28 day treatment period was
calculated for each subject. Comparisons were then made of each GW642444M dose
versus placebo using an ANCOVA model with effects due to baseline value, centre
grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Estimated treatment differences for all comparisons were presented.
Withdrawals Due to Lack of Efficacy
Fishers Exact test was used to compare the number of withdrawals due to lack of
efficacy between each GW642444M treatment group versus placebo.
5.8.9.
Safety Analyses
The analyses of the safety data are detailed in Section 12 of the RAP.
5.8.9.1.
Extent of Exposure
The extent of exposure was summarised by treatment group. Exposure was defined as
[date of last dose - date of first dose] + 1.
5.8.9.2.
Adverse Events
AEs were coded using the standard GSK dictionary MedDRA. AEs were classified as
pre-treatment, during active treatment (on-treatment) and post-treatment. Narratives for
withdrawals due to AEs were supplied.
5.8.9.3.
Vital signs (pulse rate, systolic blood pressure and diastolic blood pressure) were
summarised by treatment for each clinic visit. Additionally, the following derived vital
signs endpoints were analysed: change from baseline and pre-dose in maximum value (04 h) for systolic blood pressure, change from baseline and pre-dose in minimum value (04 h) for diastolic blood pressure, change from baseline and pre-dose in maximum value
(0-4 h) for pulse rate, and weighted mean change from baseline and pre-dose (0-4 h) for
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blood pressure and pulse rate. Pair-wise comparisons of each active treatment group
versus placebo were also performed.
The baseline for vital signs was defined as the Visit 2 pre-dose assessment. If the
baseline was missing, then the screening Visit 1 value was used in its place.
5.8.9.5.
12-Lead ECG
0-4 h post-dose QTc(F) and QTc(B), and maximum QTc(F) and QTc(B), were summarised
for Day 1, Day 7, Day 14 and Day 28. Maximum change from baseline, weighted mean
change from baseline and weighted mean change from pre-dose were also summarised.
Post-dose serial QTc(F) and QTc(B) and change from baseline endpoints were analysed
using ANCOVA as for derived vital signs endpoints (see Section 12.7.1 of the RAP).
Pair-wise comparisons of each active treatment versus placebo were performed and
treatment differences were presented.
Baseline was defined as Visit 2 pre-dose value. If the Visit 2 pre-dose assessment was
missing, then the screening Visit 1 value was used.
5.8.9.6.
Fasting serum potassium and plasma glucose data were summarised by treatment for Day
1 and Day 28 and for non-fasting potassium on Day 7 and 14, and were used to derive the
following endpoints:
Weighted mean change from baseline and pre-dose (0-4 h) for potassium.
Weighted mean change from baseline and pre-dose (0-4 h) for glucose.
Baseline was defined as Visit 2 pre-dose value. Data were analysed using ANCOVA
with effects due to baseline value, centre grouping, age, sex, baseline-predicted FEV1
stratum and treatment group. Pair-wise comparisons of each treatment group versus
placebo and summaries of change from baseline and change from pre-dose were
presented.
5.8.9.7.
Exacerbations
The number and percentage of subjects who had an asthma exacerbation, who took oral
corticosteroids for an exacerbation, who were hospitalised due to an exacerbation or who
had an emergency room visit due to an exacerbation were summarised separately
alongside the primary causes of asthma exacerbations.
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Subjects with a Novel Dry Powder Inhaler malfunction were listed with the primary
reason for malfunction.
5.8.10.
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endpoints was investigated. The systemic PK/PD analysis was conducted using the
NONMEM software (Version 5.1, Globomax, MD) within the OBIWAN interface and
database (GSK Validated System). Excel and R 2.6.2 were utilised for graphical and
summary evaluations for both PK and PK/PD analyses.
To supplement the information provided from the primary statistical analysis a
population mixed-effect dose-response analysis was performed using mean change from
baseline trough FEV1 data (evening pre-bronchodilator and pre-dose) derived from the
mean of the 23 and 24 h post-dose assessments. The ITT dataset containing observed
individual trough Day 28 FEV1 data with patient covariates was used for estimating the
dose response model parameters (including placebo effect and inter-patient variability,
potency (ED50) and maximum predicted effect (Emax). Non-linear mixed effects model
with the program NONMEM V1 Level 2.0 as implemented in PDxPop V3.10, ICON
Dev. Solns (2008) was used. Further details on the methodology and results are provided
in Attachment 4.
5.8.11.
Pharmacogenetic Analyses
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6.1.
Disposition of Subjects
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A total of 1140 subjects were screened of whom 614 (54%) were randomised (Table 3).
The most common reason for Screening failure was not meeting continuation criteria.
Table 3
1140
614 (54%)
526 (46%)
457 (40%)
29 (3%)
19 (2%)
Of the 614 randomised subjects, 607 (99%) were included in the ITT Population having
received at least one dose of study medication; 583 (95%) were included in the PP
Population (Table 4). In total, 539 (89%) subjects in the ITT Population completed the
study (Run-in to Follow-up). The most common primary reason for withdrawal from the
study was Lack of efficacy which was reported by 33 (5%) of subjects, followed by
Subject reached protocol-defined stopping criteria (18 subjects [3%]). Two (<1%)
subjects withdrew with the primary reason due to AEs.
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Table 4
3 g
GW642444
6.25 g
GW642444
12.5 g
GW642444
25 g
GW642444
Totala
Randomised,N(%)
103
102
102
102
103
ITTb, n (%)
102 (>99)
101 (>99)
101 (>99)
100 (98)
101 (98)
Lower stratumc
44 (43)
46 (46)
43 (43)
42 (42)
47 (47)
Upper stratumd
58 (57)
55 (54)
58 (57)
58 (58)
54 (53)
PPe, n (%)
98 (95)
97 (95)
98 (96)
98 (96)
93 (90)
Completion status, n (%)
Completed
86 (84)
84 (83)
91 (90)
88 (88)
93 (92)
Withdrawn
16 (16)
17 (17)
10 (10)
12 (12)
8 (8)
Primary reason for withdrawalf, n (%)
Lack of Efficacy
9 (9)
12 (12)
3 (3)
5 (5)
4 (4)
Subject reached
3 (3)
1 (<1)
7 (7)
3 (3)
2 (2)
protocol-defined
stopping criteria
Subject withdrew
3 (3)
0
0
1 (1)
1 (<1)
consent
Investigator
0
1 (<1)
0
1 (1)
0
discretion
Protocol deviation
1 (<1)
2 (2)
0
1 (1)
0
AE
0
1 (<1)
0
0
1 (<1)
Lost to Follow-up
0
0
0
1 (1)
0
Source data: Table 6.1, Table 6.3, Table 6.23.
a. Total: all subjects screened and for whom a record exists on the study database.
b. ITT: all randomised subjects who received at least a single dose of study medication.
c. Lower Stratum: FEV1 percent predicted 40% - 65%.
d. Upper stratum: FEV1 percent predicted 65% - 90%.
e. PP: all subjects in the ITT Population who did not have any full protocol deviations.
f. The primary reason for withdrawal as determined by the Investigator.
50 g
GW642444
Total
102
102 (100)
46 (45)
56 (55)
99 (97)
1140
614 (54)
607 (99)
268 (44)
339 (56)
583 (95)
97 (95)
5 (5)
539 (89)
68 (11)
0
2 (2)
33 (5)
18 (3)
1 (<1)
6 (<1)
2 (2)
4 (<1)
0
0
0
4 (<1)
2 (<1)
1 (<1)
Within the ITT Population, attendance at each clinic visit for all treatment groups was
similar (>87%) and is summarised in Table 6.4. Twenty-seven (4%) subjects were 12-17
years of age (Listing 6.4, Attachment 5) and had been recruited by centres for which no
age limit had been set.
6.2.
Protocol Deviations
Few full protocol deviations were reported for the ITT Population (24 subjects [4%]).
These included failure to meet inclusion, exclusion or randomisation criteria, use of
prohibited medications, or any other deviations deemed to have the potential for
influencing the primary endpoint (Table 6.7). The treatment group with the highest
number of full protocol deviations was the 25 g GW642444M treatment group (8
subjects [8%] within this group).
Twenty two subjects (4%) in the ITT Population had part of their data excluded from the
PP analysis due to partial protocol deviations (Table 6.7). These subjects used prohibited
medications or remained in the study after falling below the FEV1 or PEF stability limit,
after an exacerbation, or after excessive use of rescue medication. The highest number of
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partial protocol deviations were reported for the 3 g GW642444M treatment group (8
subjects [8%] within this group).
Table 6.6 displays a summary of inclusion/exclusion criteria deviations. The incidence of
these deviations was similar across the treatment groups (0-2%).
6.3.
Populations Analysed
As defined in Section 5.8.3, four populations were used for analysis: the Total
Population, the ITT and PP Populations, and the PK Concentration Population. Of the
607 subjects in the ITT Population, 102 subjects were treated with placebo, 101 with 3 g
GW642444M, 101 with 6.25 g GW642444M, 100 with 12.5 g GW642444M, 101 with
25 g GW642444M, and 102 with 50 g GW642444M.
6.4.
6.4.1.
Demographic Characteristics
Demographic characteristics were similar across the treatment groups within the ITT
Population (Table 5). The majority of subjects were female (50% to 60% across
treatment groups) and White (73% to 81% across treatment groups). The mean age was
39.9 to 44.4 years across treatment groups.
Demographic characteristics of the Per Protocol Population were similar to those reported
for the ITT Population and are provided in Table 6.9.
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Table 5
Age (years) a
Mean
SD
Range
Sex, n (%)
Female
Male
Ethnicity
Hisp/Lat
Not Hisp/Lat
Race, n (%)
White
Asian
African American / African
heritage
American Indian or
Alaska Native
Native Hawaiian or other
Pacific Islander
African American/African
Heritage & American
Indian or Alaska Native
African American/African
Heritage & White
American Indian or
Alaska Native & White
Asian & White
Height (cm)
Mean
SD
Range
Weight (kg)
Mean
SD
Range
N=102
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
39.9
15.60
12-68
44.4
13.50
15-74
42.4
14.13
16-80
41.3
15.33
12-72
42.2
14.27
12-70
44.0
15.22
13-73
61 (60)
41 (40)
52 (51)
49 (49)
51 (50)
50 (50)
56 (56)
44 (44)
61 (60)
40 (40)
57 (56)
45 (44)
9 (9)
93 (91)
13 (13)
88 (87)
10 (10)
91 (90)
13 (13)
87 (87)
12 (12)
89 (88)
22 (22)
80 (78)
81 (79)
11 (11)
4 (4)
74 (73)
13 (13)
11 (11)
77 (76)
11 (11)
8 (8)
75 (75)
8 (8)
12 (12)
75 (74)
9 (9)
14 (14)
83 (81)
9 (9)
8 (8)
3 (3)
2 (2)
3 (3)
2 (2)
2 (2)
1 (<1)
1 (<1)
1 (<1)
2 (2)
1 (<1)
1 (<1)
2 (2)
1 (<1)
1 (<1)
1 (1)
165.3
10.94
108-188
169.5
11.30
135-200
167.3
9.67
149-193
168.5
10.06
140-191
167.1
9.70
150-193
167.8
9.97
147-198
77.16
78.98
77.58
81.53
77.09
78.93
18.644
17.625
17.731
19.063
18.702
20.652
48.043.0-142.0
50.0-127.3
30.9-137.3
43.0-134.1
44.5-155.9
127.0
Source data: Table 6.8 and Table 6.10.
a. 27 subjects [4%] were 12 - 17 years of age: 7 in the placebo group, 2 in the 3 g GW642444M group, 2 in the
6.25 g GW642444M group, 7in the 12.5 g GW642444M group, 5 in the 25 g GW642444M group, 4 in the 50
g GW642444M group.
Hisp/Lat = Hispanic/Latino.
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6.4.2.
Other Characteristics
6.4.2.1.
Tobacco History
The history of tobacco use within the ITT Population captured at Screening is provided in
Table 6.12. The majority of subjects (79% to 86%) across all treatment groups reported
to have never smoked prior to taking part in the study.
6.4.2.2.
Asthma History
A summary of the duration of asthma and asthma history is summarised in Table 6. All
treatment groups had a similar duration of asthma and the majority of subjects across
treatment groups had a history of asthma 10 years or more in duration (64% to 74%).
The majority of subjects (67%) had a history of atopy (Table 6.13).
Table 6
<6 months
6 months to <1 year
1 year to <5 years
5 years to <10 years
10 years
Source Table 6.13.
6.4.2.3.
N=102
0
0
14 (14)
20 (20)
68 (67)
3 g
GW642444
N=101
0
2 (2)
11 (11)
13 (13)
75 (74)
6.25 g
GW642444
N=101
0
1 (<1)
19 (19)
11 (11)
70 (69)
12.5 g
GW642444
N=100
0
1 (1)
16 (16)
12 (12)
71 (71)
25 g
GW642444
N=101
0
2 (2)
11 (11)
14 (14)
74 (73)
50 g
GW642444
N=102
0
1 (<1)
16 (16)
20 (20)
65 (64)
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Table 7
N=102
Pre-Bronchodilator FEV1, (L)
Mean
2.211
SD
0.6740
Min-Max
0.83-4.48
Percent Predicted FEV1, (%)
Mean
66.9
SD
11.97
Min-Max
41-90
Post-Bronchodilator FEV1, (L)
Mean
2.767
SD
0.8004
Min-Max
1.18-5.26
Percent Reversibility in FEV1, (%)
Mean
26.6
SD
15.37
Min-Max
7-86
Absolute Reversibility in FEV1, (mL)
Mean
555.5
SD
300.26
Min-Max
164-1697
Source data: Table 6.21.
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
2.257
0.8031
1.04-4.54
2.243
0.6494
1.06-3.63
2.255
0.6315
1.03-4.02
2.127
0.6067
0.83-3.76
2.165
0.6143
0.86-4.37
65.8
13.48
40-90
66.5
10.75
42-88
67.6
11.79
41-90
65.3
12.08
42-89
65.9
12.29
40-89
2.775
0.9468
1.26-5.17
2.806
0.7814
1.45-4.59
2.792
0.7369
1.32-4.81
2.668
0.7027
1.32-4.23
2.702
0.7095
1.07-5.05
24.2
13.45
2-76
26.3
15.39
6-100
25.2
16.20
12-125
27.4
20.74
12-123
26.4
15.45
-12-102
517.8
271.20
29-1317
562.7
291.05
148-1564
537.0
280.18
201-1501
540.2
339.07
200-2207
537.0
253.50
-229-1427
When split by stratum based on percent predicted FEV1, 53% to 58% of subjects in the
ITT Population were included in the upper stratum (Table 6.23). Within the strata, mean
percent predicted FEV1 was similar across the treatment groups and ranged from 75.5%
to 78.3% within the upper stratum; for the lower stratum this was 54.2% to 57.8%
(Table 6.24).
6.4.3.
Medical conditions present within the ITT Population at Screening are presented in
Attachment 1. A total of 485 (80%) subjects presented with current medical conditions.
In general, the distribution of current medical disorders was similar across the treatment
groups. The most frequent medical conditions were Respiratory, thoracic and
mediastinal disorders (42% of ITT Population subjects), followed by nervous system
disorders (20% of subjects), musculoskeletal and connective tissue disorders (20% of
subjects) and hypersensitivity/anaphylaxis related disorders (18% of subjects).
6.5.
Concomitant Medications
6.5.1.
The types of pre-, on- and post-treatment asthma medications are summarised in
Table 6.15, Table 6.16 and Table 6.17, respectively.
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Prior to study treatment, all subjects were taking asthma medication; the use of asthma
medication was similar across all treatment groups. The most frequently taken asthma
medications pre-study were salbutamol, fluticasone propionate and budesonide, which
were taken by 70%-79%, 32%-44% and 35%-48% of subjects across treatment groups,
respectively.
During treatment, asthma medications were taken by >99% to 100% of subjects across
the treatment groups (Table 8). In general, the percentage of subjects taking concomitant
asthma medications on-treatment was similar across the groups. This was also observed
for post-treatment asthma medications (Table 6.17). Both on- and post-treatment the
most frequently reported asthma medications were fluticasone propionate (32% - 44% of
subjects across treatment groups), budesonide (33%-48%), and beclomethasone
dipropionate and beclometasone (11%-22%).
During treatment, 3 subjects received oral corticosteroids. These subjects were excluded
from the PP Population.
Table 8
n (%)
Any medication
3 g
GW642444
N=101
101 (100)
6.25 g
GW642444
N=101
101 (100)
12.5 g
GW642444
N=100
100 (100)
25 g
GW642444
N=101
100 (>99)
50 g
GW642444
N=102
102 (100)
Fluticasone propionate
37 (37)
41 (41)
44 (44)
42 (42)
33 (32)
Budesonide
48 (48)
35 (35)
35 (35)
33 (33)
36 (35)
Beclometasone
11 (11)
22 (22)
11 (11)
13 (13)
20 (20)
dipropionate and
beclometasone
Mometasone furoate
4 (4)
1 (<1)
1 (<1)
7 (7)
6 (6)
7 (7)
Ciclesonide
4 (4)
3 (3)
2 (2)
2 (2)
5 (5)
5 (5)
Salbutamola
2 (2)
6 (6)
2 (2)
4 (4)
4 (4)
0
Source Table 6.16.
Some subjects took more than one concomitant medication.
a. Although the Investigators were instructed not to record the use of rescue medication as concomitant medication,
the use of albuterol/salbutamol was recorded by some Investigators.
6.5.1.1.
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Table 9
BDP-equivalent daily
dose (g)
Placebo
N=102
n
94
Mean
814.4
SD
537.50
Median
800.0
Min-Max
100-2000
Source data: Table 6.103.
BDP = beclometasone dipropionate.
6.5.2.
3 g
GW642444
N=101
89
698.3
405.53
500.0
200-2000
6.25 g
GW642444
N=101
84
747.6
467.68
550.0
100-2000
12.5 g
GW642444
N=100
91
736.3
473.29
500.0
100-2000
25 g
GW642444
N=101
92
736.4
411.78
800.0
200-2000
50 g
GW642444
N=102
92
709.8
517.24
500.0
100-2000
The types of pre-, on- and post-treatment non-asthma medications are summarised in
Table 6.18, Table 6.19 and Table 6.20, respectively.
In general, prior to study treatment, non-asthma medications were taken by the majority
of subjects (48% to 68%) across the treatment groups. Paracetamol was the most
frequently taken (9% to 13% of subjects across treatment groups), followed by ibuprofen,
vitamins (NOS), fluticasone propionate, mometasone furoate and acetylsalicylic acid.
Intranasal and topical formulations of fluticasone propionate and mometasone furoate
were taken as a non-asthma medication. Pre-treatment non-asthma medications were
taken to a similar extent across treatment groups.
During treatment, non-asthma medications were taken by 57% - 72% of subjects across
treatment groups. The most frequently recorded concurrent non-asthma medication
during treatment was paracetamol (taken by 13% to 17% of subjects across treatment
groups), followed by ibuprofen, vitamins (NOS), fluticasone propionate (intranasal and
topical formulation) and acetylsalicylic acid. In general, the percentage of subjects taking
concurrent non-asthma medications during the treatment period was similar across the
treatment groups.
Non-asthma medications taken post-treatment were recorded for 50% to 67% of subjects
across treatment groups. As was observed during treatment, the most frequently recorded
post-treatment non-asthma medication was paracetamol (taken by 6% to 11% of subjects
across treatment groups). Ibuprofen, fluticasone propionate (intranasal and topical
formulation), vitamins (NOS), acetylsalicylic acid and mometasone furoate (intranasal
and topical formulation) were also frequently taken.
6.6.
Treatment Compliance
Treatment compliance, as assessed at Visits 2 through 5, was similar across all treatment
groups in the ITT Population. Mean overall compliance for the treatment groups was
high and similar across the treatment groups, and ranged from 98.9% to 107% (Table 10).
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Most of the over-compliance (>100%) was near 100%. Post-hoc analysis showed that
only 13 subjects recorded treatment compliance of greater than 110%, including one
subject with compliance of 633% in the placebo group who was withdrawn early due to
lack of efficacy (Listing 6.101, Attachment 5). This subject was in the study for a short
period of time (three days) and thus a few actuations more than the expected number
during the duration of treatment inflates the compliance level by a significant amount.
Approximately half (6 of 13) of the subjects with compliance values over 110% withdrew
early from the study either due to lack of efficacy (2 subjects), subject reaching protocoldefined stopping criteria (2 subjects) or withdrawn consent (2 subjects) (Listing 6.101,
Attachment 5). These subjects who withdrew early were in the study for 13 days.
Table 10
Placebo
N=102
102
107.0
54.72
100.00
79-633
3 g
GW642444
N=101
101
99.3
4.83
100.00
83-115
6.25 g
GW642444
N=101
101
98.9
5.58
100.00
81-125
12.5 g
GW642444
N=100
100
99.5
4.03
100.00
83-111
25 g
GW642444
N=101
100
99.0
5.59
100.00
75-112
50 g
GW642444
N=102
101
99.6
4.08
100.00
83-107
102
1 (<1)
77 (75)
24 (24)
101
0
75 (74)
26 (26)
101
0
82 (81)
19 (19)
100
0
79 (79)
21 (21)
100
3 (3)
79 (79)
18 (18)
101
0
77 (76)
24 (24)
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7.
EFFICACY RESULTS
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The primary efficacy endpoint was the mean change from baseline in clinic visit trough
(pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period, with
the trough FEV1 defined as the mean of the 23 and 24 h post-dose assessments at Day 28.
In order to demonstrate overall efficacy of GW642444M relative to placebo, the primary
treatment comparison was a test of linear dose response in trough (pre-bronchodilator and
pre-dose) FEV1 at Day 28 across the five doses of GW642444M and placebo. The ITT
Population was the primary population of interest for the primary efficacy analysis.
The results of the linear trend test of change from baseline in trough FEV1 at the end of
the treatment period using LOCF are summarised in Table 11. Overall efficacy of
GW642444M relative to placebo was demonstrated by a statistically significant linear
trend test (p=0.003), indicating that the slope of the dose-response relationship was not
zero. When the same linear trend test was performed excluding placebo to investigate the
dose response across the five doses of GW642444M, a significant dose response
(p=0.037) was found. The dose-response curve based on linear trend test is shown in
Figure 2.
Table 11
0.003
2.545 mL/g
(0.893, 4.196)
0.037
1.924 mL/g
(0.120, 3.728)
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Figure 2
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Since the test of linear trend was statistically significant, pair-wise tests of each dose
versus placebo were performed to identify effective doses (Table 12). Although a
placebo effect was observed (LS mean change of 0.147 L in FEV1 from baseline), tests of
each GW642444M dose versus placebo demonstrated a statistically significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo (mean
treatment differences of 0.130 L, 0.121 L and 0.162 L, respectively).
The adjusted treatment differences and corresponding 95% confidence intervals (CIs) for
change from baseline in trough FEV1 at the end of the treatment period are shown in
Figure 3.
Figure 7.3 is a box plot of change from baseline in trough FEV1.
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Table 12
Day 28
Placebo
n
LS Mean
LS Mean Change
(SE)
Difference vs. placebo
95% CI
p-value
Source Table 7.4.
Figure 3
N=102
95
2.388
0.147
(0.036)
3 g
GW642444
N=101
98
2.452
0.212
(0.036)
0.064
-0.036,0.164
0.208
6.25 g
GW642444
N=101
99
2.458
0.217
(0.035)
0.069
-0.029,0.168
0.169
12.5 g
GW642444
N=100
97
2.518
0.278
(0.036)
0.130
0.030,0.230
0.011
25 g
GW642444
N=101
99
2.509
0.269
(0.035)
0.121
0.023,0.220
0.016
50 g
GW642444
N=102
100
2.550
0.309
(0.035)
0.162
0.062,0.261
0.001
7.1.1.
7.1.1.1.
PP Population
The analyses of the primary endpoint (linear trend test and pair-wise comparisons of the
GW642444M doses with placebo) were repeated for the PP Population. Table 7.5
summarises the trough FEV1 for the PP Population and the change from baseline in
trough FEV1 at the end of the 28-day treatment period. Table 7.6 shows the results of the
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linear trend test of change from baseline in trough FEV1, and the statistical analysis of
change from baseline in trough FEV1 for the PP Population is summarised in Table 7.7.
These data are depicted graphically in Figure 4 and Figure 7.6 and Figure 7.7.
The results of the analyses of the primary efficacy measure for the PP Population were
consistent with those for the ITT Population and showed statistically significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo (mean
treatment differences of 0.118 L [p=0.022], 0.135 L [p=0.008], and 0.135 L [p=0.008],
respectively).
Figure 4
7.1.1.2.
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These results are shown graphically in Figure 5. An increase in FEV1 was noted on Day
29 following dosing on Day 28, which may be due to this treatment being supervised on
Day 28 in contrast to the treatment taken before the Day 7 and Day 14 measurements.
Figure 5
7.2.
7.2.1.
In order to investigate the consistency of the dose-response relationship for the different
disease severities, the change from baseline in trough FEV1 at the end of the treatment
period was analysed for each stratum (Table 13). Within each GW642444M dose, the
upper and lower strata responded in a similar manner showing similar dose responses,
with the confidence intervals overlapping the LS mean change for all groups except 3 g.
The adjusted treatment differences for each stratum are presented in Figure 6.
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Table 13
Day 28
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3 g
6.25 g
GW642444
GW642444
N=102
N=101
N=101
Lower stratum (FEV1 percent predicted 40% - 65%)
n
43
44
41
LS Mean
2.450
2.402
2.487
LS Mean
0.210(0.057) 0.161(0.056) 0.247(0.057)
Change (SE)
Difference
-0.049
0.037
vs. Placebo
95% CI
((0.198,0.100)
0.113,0.188)
Upper stratum (FEV1 percent predicted 65% - 90%)
n
52
54
58
LS Mean
2.338
2.495
2.435
LS Mean
0.098(0.049) 0.254(0.051) 0.194(0.048)
Change (SE)
Difference
0.156
0.097
vs. Placebo
95% CI
(0.022,0.291)
(0.035,0.228)
Source data: Table 7.13.
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12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
40
2.559
0.319(0.057)
46
2.522
0.281(0.054)
45
2.590
0.349(0.055)
0.109
0.072
0.139
(-0.044,0.262)
(-0.075,0.218)
(-0.009,0.287)
57
2.488
0.247(0.049)
53
2.499
0.259(0.049)
55
2.517
0.276(0.049)
0.149
0.161
0.178
(0.018,0.281)
(0.027,0.295)
(0.045,0.312)
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Figure 6
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7.2.2.
The change from baseline in weighted mean for 24-h serial FEV1 on Days 1 and 28 was
compared for each GW642444M group versus placebo, with the 6-12 h post-dose time
points only measured in a subset of subjects.
Analysis of all ITT Population subjects (including those with the additional time point
measurements at 6 and 12 h after dosing) demonstrated that all GW642444M treatments
showed statistically significant improvement in FEV1 compared with placebo on Days 1
and 28, with the exception of 6.25 g GW642444M on Day 1 (Table 14 and Figure 7).
On both Days, a dose response was observed with the greatest improvements from
baseline in 24-h serial FEV1 versus placebo in the 12.5 g GW642444M group (0.130 L
on Day 1 and 0.142 L on Day 28), the 25 g GW642444M group (0.193 L on Day 1 and
0.165 L on Day 28) and the 50 g GW642444M group (0.215 L on Day 1 and 0.172 L on
Day 28).
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A summary of the weighted mean change from baseline is presented in Table 7.19.
Table 14
Statistical Analysis of Weighted Mean Change from Baseline in 24hour Serial FEV1 (L) (All Subjects, including 6-12 hour Time Points)
(ITT Population)
Placebo
N=102
Day 1
n
101
LS Mean (SE)
0.137(0.029)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.149(0.032)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.20.
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
100
0.239(0.029)
0.102
101
0.215(0.029)
0.078
99
0.267(0.029)
0.130
100
0.330(0.029)
0.193
100
0.352(0.029)
0.215
(0.020,0.183)
0.015
(-0.003,0.158)
0.059
(0.049,0.211)
0.002
(0.112,0.273)
<0.001
(0.134,0.296)
<0.001
83
0.300(0.033)
0.151
91
0.253(0.031)
0.103
88
0.292(0.032)
0.142
93
0.315(0.031)
0.165
97
0.321(0.031)
0.172
(0.059,0.242)
0.001
(0.014,0.192)
0.023
(0.052,0.232)
0.002
(0.077,0.253)
<0.001
(0.084,0.260)
<0.001
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Figure 7
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Day 1
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Figure 7
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Day 28
Impact of the 6-12 hour Time Points on Weighted Mean Serial FEV1
A sensitivity analysis was performed for the ITT Population on Days 1 and 28 to assess
the impact of the 6-12 h time points on the changes in weighted mean serial FEV1 from
baseline following treatment (Table 7.21, Table 7.22 and Table 7.23). This was
performed to assess the impact of the 34% of subjects not providing FEV1 measurements
at 6 h and 12 h post-dose5. The estimated treatment differences for the comparisons of
the GW642444M treatments with placebo for Day 28 are presented in Figure 8. These
analyses demonstrate that exclusion of the 6-12 h timepoints does not have a substantial
impact on the treatment differences.
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Figure 8
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A further sensitivity analysis was performed to assess whether rescue medication affected
weighted mean 24-h serial FEV1 values measured following GW642444M treatment on
Days 1 and 28. The analysis as that described for weighted mean 24-h serial FEV1 was
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performed after removing the FEV1 measurements taken within 6 h after rescue
medication use6 (Table 7.24). These results were similar to those from the full analysis.
7.2.3.
The change from baseline in daily PM trough (pre-dose and pre-rescue bronchodilator)
PEF averaged over the 28-day treatment period was compared for each GW642444M
dose vs. placebo (Table 15 and Figure 9). Figure 10 shows the daily mean change from
baseline in PM PEF.
Statistical analysis of change from baseline over Days 1-28 (Table 15 and Figure 9)
showed that all GW642444M treatment groups had statistically significantly greater
improvements in PM PEF compared with placebo, demonstrating a sustained
bronchodilatory effect. The greatest increases in PM PEF were recorded for the 25 g
and 50 g GW642444M groups (33.6 L/min and 38.0 L/min, respectively. The
GW642444M treatments were numerically better than placebo from the first week of
treatment onwards (Table 7.39).
Table 15
n
LS Mean
LS Mean Change (SE)
Difference versus Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.40.
N=102
99
378.3
0.4 (3.87)
3 g
GW642444
N=101
99
391.9
14.0 (3.87)
6.25 g
GW642444
N=101
101
402.4
24.5 (3.82)
12.5 g
GW642444
N=100
98
406.7
28.9 (3.87)
25 g
GW642444
N=101
101
411.8
34.0 (3.81)
50 g
GW642444
N=102
102
416.2
38.4 (3.82)
13.6
(2.8, 24.4)
0.014
24.1
(13.5, 34.8)
<0.001
28.5
(17.7, 39.3)
<0.001
33.6
(22.9, 44.2)
<0.001
38.0
(27.3, 48.7)
<0.001
Subjects were requested not to use their rescue albuterol/salbutamol for at least 6 h prior to the clinic visit
during which spirometry was performed, if possible. However some subjects had used rescue
medication within 6 h of the assessment. These subjects were not excluded from ITT analysis.
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Figure 9
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Figure 10
7.2.4.
The statistical analysis of change from baseline in daily AM PEF averaged over the 28day treatment period for each GW642444M dose versus placebo is summarised in
Table 16. The daily mean change from baseline in AM PEF is presented graphically in
Figure 11.
As was observed for PM PEF, all GW642444M treatment groups experienced
statistically significantly greater improvements in AM PEF compared with placebo. AM
PEF increased with GW642444M dose, with the greatest improvements versus placebo in
the 25 g and 50 g GW642444M groups (36.2 L/min and 42.1 L/min, respectively) The
GW642444M treatments were numerically better than placebo from the first week of
treatment onwards (Table 7.41).
Table 16
n
LS Mean
LS Mean Change (SE)
Difference versus Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.42.
N=102
98
364.7
1.9 (3.69)
3 g
GW642444
N=101
99
381.4
18.7 (3.67)
6.25 g
GW642444
N=101
101
389.5
26.8 (3.63)
12.5 g
GW642444
N=100
98
397.0
34.2 (3.68)
25 g
GW642444
N=101
101
400.9
38.1 (3.61)
50 g
GW642444
N=102
102
406.7
44.0 (3.63)
16.8
(6.5, 27.1)
0.001
24.9
(14.7, 35.1)
<0.001
32.3
(22.1, 42.6)
<0.001
36.2
(26.1, 46.4)
<0.001
42.1
(31.9, 52.2)
<0.001
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Figure 11
7.2.5.
The changes from baseline in the percentage of symptom-free 24-h periods over the 28day treatment period were compared for each GW642444M dose versus placebo. The
statistical analysis of change from baseline in the percentage of symptom-free 24-h
periods over Days 1-28 is summarised in Table 17 and Figure 12. When compared with
placebo, the differences from baseline were statistically significant for all GW642444M
treatments except for 3 g GW642444M. A dose-response effect was observed with the
greatest increases in percentage symptom-free periods in the 25 g and 50 g
GW642444M groups (22.2% and 18.1%, respectively).
Table 17
n
LS Mean Change (SE)
Difference vs Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.44.
N=102
98
14.2 (3.27)
3 g
GW642444
N=101
99
22.6 (3.25)
6.25 g
GW642444
N=101
101
23.6 (3.21)
12.5 g
GW642444
N=100
98
26.8 (3.26)
25 g
GW642444
N=101
101
36.4 (3.21)
50 g
GW642444
N=102
102
32.3 (3.21)
8.4
(-0.7, 17.5)
0.069
9.4
(0.4, 18.4)
0.040
12.7
(3.6, 21.8)
0.006
22.2
(13.3, 31.2)
<0.001
18.1
(9.1, 27.2)
<0.001
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Figure 12
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7.2.6.
The statistical analysis of change from baseline in the percentage of rescue-free 24-h
periods over Days 1-28 is summarised in Table 18 and Figure 13. When compared with
placebo, the differences from baseline were statistically significant for all GW642444M
treatments. A dose-response effect was observed with the greatest increases in
percentage rescue-free periods in the 25 g and 50 g GW642444M groups (28.4% and
19.0%, respectively).
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Table 18
n
LS Mean Change (SE)
Difference vs Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.46.
Figure 13
N=102
99
15.0 (3.33)
3 g
GW642444
N=101
99
25.8 (3.33)
6.25 g
GW642444
N=101
101
27.3 (3.28)
12.5 g
GW642444
N=100
98
29.6 (3.34)
25 g
GW642444
N=101
101
43.4 (3.28)
50 g
GW642444
N=102
102
34.0 (3.28)
10.8
(1.5, 20.1)
0.023
12.3
(3.1, 21.5)
0.009
14.7
(5.4, 24.0)
0.002
28.4
(19.3, 37.6)
<0.001
19.0
(9.8, 28.3)
<0.001
7.2.7.
Post-Salbutamol/Albuterol FEV1
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Statistical analysis (Table 19) showed no significant differences in postsalbutamol/albuterol FEV1 for any of the time intervals against placebo for any
GW642444M treatment. The fact that the mean treatment differences are close to zero
and the corresponding CIs surrounding zero indicates that tolerance had not developed
over the 28-day treatment period.
Table 19
N=102
Day 28 - Day 1
n
83
LS Mean
-0.039(0.023)
(SE)
Difference vs
Placebo
95% CI
p-value
Day 1 Screening
n
97
LS Mean
-0.040(0.028)
(SE)
Difference vs
Placebo
95% CI
p-value
Day 28 Screening
n
84
LS Mean
-0.076(0.031)
(SE)
Difference vs
Placebo
95% CI
p-value
Source data: Table 7.27.
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
80
-0.035(0.024)
87
-0.012(0.023)
86
-0.017(0.023)
86
-0.062(0.023)
92
-0.049(0.022)
0.004
0.027
0.022
-0.023
-0.010
(-0.062,0.069)
0.916
(-0.037,0.091)
0.410
(-0.042,0.087)
0.498
(-0.087,0.041)
0.482
(-0.074,0.054)
0.756
97
0.008(0.028)
98
-0.061(0.028)
99
-0.029(0.028)
96
-0.020(0.028)
98
-0.060(0.028)
0.047
-0.021
0.011
0.020
-0.020
(-0.032,0.126)
0.241
(-0.099,0.057)
0.598
(-0.067,0.089)
0.791
(-0.058,0.098)
0.619
(-0.099,0.058)
0.613
80
-0.022(0.031)
89
-0.055(0.030)
86
-0.048(0.030)
88
-0.086(0.030)
93
-0.104(0.029)
0.055
0.021
0.029
-0.009
-0.027
(-0.032,0.141)
0.217
(-0.062,0.105)
0.615
(-0.056,0.114)
0.507
(-0.093,0.075)
0.826
(-0.111,0.056)
0.519
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7.3.
7.3.1.
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Repeated measures analysis of the adjusted treatment differences from placebo over time
demonstrated a sustained, 24-h duration of action on Day 1 (Table 7.17, Figure 7.20), as
well as on Day 28 (Table 7.18, Figure 14) for all GW642444M treatments.
Figure 14
7.3.2.
For each GW642444M dose, the weighted mean change and maximum increase in FEV1
(0-4 h) from baseline on Days 1 and 28 were compared with placebo.
Table 20 shows that on Days 1 and 28 weighted mean change from baseline in FEV1 (0-4
h) differences with placebo were statistically significant for all GW642444M treatments.
Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, consistently higher
increases in weighted mean FEV1 versus placebo were recorded for 25 g GW642444M
(0.226 L on Day 1 and 0.205 L on Day 28) and 50 g GW642444M (0.236 L on Day 1
and 0.213 L on Day 28).
For maximum increase from baseline in FEV1 (0-4 h) differences from placebo reached
statistical significance for 12.5 g, 25 g, and 50 g GW642444M on Day 1, and for all
doses except 6.25 g GW642444M on Day 28 (Table 21). As for weighted mean change
in FEV1 (0-4 h), consistently higher increases in maximum FEV1 were recorded for the
25 g and 50 g GW642444M groups compared with the other treatments.
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Plots of the absolute and percentage change from baseline in serial FEV1 (0-4 h) on Day 1
and 28 are presented in Table 7.15 and Table 7.16 and in Figure 7.16 and Figure 7.17,
and Figure 15).
Table 20
N=102
Day 1
n
101
LS Mean (SE)
0.095(0.027)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.136(0.033)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.31.
Table 21
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
101
0.202(0.027)
0.107
101
0.176(0.027)
0.081
99
0.268(0.027)
0.173
100
0.321(0.027)
0.226
101
0.331(0.027)
0.236
(0.031,0.183)
0.006
(0.005,0.156)
0.037
(0.097,0.249)
<0.001
(0.151,0.302)
<0.001
(0.160,0.312)
<0.001
83
0.281(0.034)
0.145
91
0.246(0.032)
0.110
88
0.296(0.033)
0.160
93
0.341(0.032)
0.205
98
0.349(0.031)
0.213
(0.051,0.238)
0.003
(0.019,0.201)
0.018
(0.068,0.252)
<0.001
(0.115,0.295)
<0.001
(0.123,0.302)
<0.001
N=102
Day 1
n
102
LS Mean (SE)
0.230(0.029)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.253(0.034)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.29.
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
101
0.309(0.029)
0.079
101
0.291(0.029)
0.061
100
0.385(0.029)
0.155
101
0.439(0.029)
0.209
101
0.459(0.029)
0.228
(-0.003,0.161)
0.059
(-0.020,0.142)
0.142
(0.073,0.236)
<0.001
(0.128,0.290)
<0.001
(0.146,0.310)
<0.001
85
0.366(0.034)
0.113
91
0.333(0.033)
0.079
88
0.390(0.033)
0.137
93
0.430(0.032)
0.176
98
0.442(0.032)
0.189
(0.019,0.208)
0.019
(-0.013,0.172)
0.091
(0.044,0.230)
0.004
(0.085,0.268)
<0.001
(0.098,0.280)
<0.001
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Figure 15
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Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours (ITT
Population), Day 28
The proportion and cumulative proportion of subjects obtaining both 200 mL and 12%
increase from baseline in FEV1 0-4 h post-dosing was calculated for Days 1 and 28. The
proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
increased with GW642444M dose (Table 7.32). Within the 25 g GW642444M and 50
g GW642444M groups, 35%-36% of subjects obtained the 200 mL and 12% increase
in FEV1 by 15 minutes after dosing on Day 1. A similar dose-response effect was seen
on Day 28; of note is that on Day 28, in the highest GW642444M dose strengths 46% of
subjects in the 25 g and 50 g GW642444M groups had already obtained a 200 mL
and 12% increase from baseline in FEV1 at pre-dose (Table 7.32).
As a post-hoc analysis, the 0-4 h interval was expanded to calculate the proportion of
subjects obtaining 200 mL and 12% increase from baseline in FEV1 over 24 h
(Table 7.105 and Figure 16). On both Days 1 and 28, the majority of subjects (>50% for
most timepoints over this interval) in the 25 g GW642444M and 50 g GW642444M
groups maintained a 24-h duration of action of 200 mL and 12% above baseline.
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Figure 16
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Proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4 hours)
Results for the proportion of subjects obtaining 15% increase from baseline in FEV1 (04 h) were similar to those observed for 200 mL and 12% increase from baseline in
FEV1 (0-4 h) (Table 7.34).
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A summary and statistical analysis of peak post-dose FEV1 0-4 h following dosing on
Day 28 is presented in Table 7.36 and Table 7.37. The difference in peak post-dose
FEV1 with placebo was statistically significant for all doses except 6.25 g
GW642444M. A dose-response effect was observed with the 25 g and 50 g
GW642444M groups recording the greatest peak post-dose FEV1 (0.177 L and 0.198 L,
respectively; both p<0.001) (Table 7.37 and Figure 17).
Figure 17
On Day 28, the mean ratio of peak post-dose to trough FEV1 was similar across the
treatment groups including placebo (ranging from 1.040 in the 6.25 g GW642444M
group to 1.060 in the 50 g GW642444M group), demonstrating sustained
bronchodilation at 24-h with GW642444M (Table 22).
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Table 22
Day 28
Placebo
N=102
Ratio
n
86
Mean
1.042
SD
0.0912
Median
1.031
Minimum
0.78
Maximum
1.36
Source data: Table 7.38.
7.3.3.
3 g
GW642444
N=101
6.25 g
GW642444
N=101
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
84
1.045
0.0682
1.036
0.81
1.35
91
1.040
0.0533
1.028
0.97
1.25
88
1.043
0.0843
1.032
0.63
1.32
93
1.056
0.0718
1.048
0.92
1.34
96
1.060
0.0607
1.050
0.96
1.24
A summary and statistical analysis of the change from baseline in the percentage of
symptom-free days over the treatment period is provided in Table 7.47 and Table 23,
respectively. For symptom-free nights this information is presented in Table 7.49 and
Table 24.
Over Days 1-28, the mean change from baseline in the percentage of symptom-free days
and nights generally increased across the GW642444M treatment groups. The difference
versus placebo was greatest for the 25 g GW642444M groups (20.3% for symptom-free
days and 17.1% for symptom-free nights).
Table 23
N=102
n
99
LS Mean (SE)
15.8 (3.24)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.48.
Table 24
3 g
GW642444
N=101
99
22.5 (3.24)
6.7
(-2.3, 15.8)
0.146
6.25 g
GW642444
N=101
101
26.9 (3.20)
11.1
(2.2, 20.0)
0.015
12.5 g
GW642444
N=100
98
27.1 (3.25)
11.4
(2.3, 20.4)
0.014
25 g
GW642444
N=101
101
36.1 (3.20)
20.3
(11.4, 29.2)
<0.001
50 g
GW642444
N=102
102
34.4 (3.19)
18.6
(9.6, 27.6)
<0.001
N=102
n
98
LS Mean (SE)
13.2 (3.04)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.50.
3 g
GW642444
N=101
99
18.2 (3.02)
5.0
(-3.5, 13.4)
0.249
6.25 g
GW642444
N=101
101
19.7 (2.98)
6.5
(-1.9, 14.8)
0.128
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GW642444
N=100
98
23.1 (3.03)
9.9
(1.4, 18.3)
0.022
25 g
GW642444
N=101
101
30.3 (2.98)
17.1
(8.8, 25.4)
<0.001
50 g
GW642444
N=102
102
23.2 (2.98)
10.0
(1.6, 18.4)
0.020
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7.3.4.
A summary and statistical analysis of the change from baseline in the percentage of
rescue-free days and rescue-free nights over the treatment period are provided in
Table 7.51, and Table 7.53 and Table 25 and Table 26.
Results for the percentage of rescue-free days and nights over Day 1-28 were similar to
those observed for symptom-free days and nights. For all GW642444M groups except 3
g GW642444M, the percentage of rescue-free days was statistically significantly greater
than placebo, with the greatest differences versus placebo recorded for the 25 g
GW642444M group (25.6%). Similar results were found for rescue-free nights, with a
24.1% increase in rescue-free nights with 25 g GW642444M.
Table 25
N=102
n
99
LS Mean (SE)
15.3 (3.29)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.52.
Table 26
6.25 g
GW642444
N=101
101
29.6 (3.25)
14.2
(5.2, 23.3)
0.002
12.5 g
GW642444
N=100
98
26.2 (3.30)
10.9
(1.7, 20.0)
0.020
25 g
GW642444
N=101
101
41.0 (3.24)
25.6
(16.6, 34.7)
<0.001
50 g
GW642444
N=102
102
34.5 (3.24)
19.2
(10.1, 28.3)
<0.001
n
LS Mean (SE)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.54.
7.3.5.
3 g
GW642444
N=101
99
23.4 (3.29)
8.0
(-1.2, 17.2)
0.087
N=102
98
12.6 (3.05)
3 g
GW642444
N=101
99
19.2 (3.03)
6.7
(-1.8, 15.1)
0.123
6.25 g
GW642444
N=101
101
22.6 (2.99)
10.0
(1.6, 18.4)
0.020
12.5 g
GW642444
N=100
98
24.0 (3.04)
11.4
(3.0, 19.9)
0.008
25 g
GW642444
N=101
101
36.7 (2.98)
24.1
(15.7, 32.5)
<0.001
50 g
GW642444
N=102
102
27.5 (2.98)
14.9
(6.5, 23.3)
<0.001
A numerically higher percentage of subjects were withdrawn due to lack of efficacy from
the 3 g GW642444M group (12 [12%] subjects) and the placebo group (9 [9%]
subjects), compared with the other treatment groups (0% to 5% of subjects) (Table 7.55).
No subjects were withdrawn due to lack of efficacy in the 50 g GW642444M group.
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7.4.
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Efficacy Summary
For the primary analysis, the test of linear trend in dose response in trough FEV1
showed a statistically significant linear trend.
Supporting analyses of the primary efficacy measures (linear trend test and pair-wise
comparisons of the GW642444M doses with placebo) using the PP Population
confirmed the primary results, demonstrating a dose response with significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo.
Treatment with these doses resulted in FEV1 increases of 0.118 L, 0.135 L and 0.135
L relative to placebo, respectively.
The results of the supporting repeated measures analysis of the primary endpoint
were consistent with those of the LOCF analyses for this population and further
demonstrated a sustained, 24-h duration of action with GW642444M. The linear
trend test of change from baseline in trough FEV1 using repeated measures analysis
was statistically significant and subsequent analysis of pair-wise comparisons of
GW642444M doses with placebo showed a dose-dependent superiority of the 12.5
g, 25 g and 50 g GW642444M doses. There were statistically significant
improvements in trough FEV1 compared with placebo for 12.5 g and 25 g
GW642444M at 23 and 24 h post-dose on Day 28 as well as for 50 g GW642444M
pre-dose on Day 7, Day 14 and Day 28, and at 23-24 h post-dose on Day 28.
Whilst all GW642444M doses significantly improved weighted mean change from
baseline in 24-h serial FEV1 compared with placebo on Days 1 and 28 (with the
exception of 6.25 g GW642444M on Day 1), the greatest improvements in lung
function were observed for the 12.5 g, 25 g and 50 g GW642444M groups
(0.130 L, 0.193 L and 0.215 L respectively on Day 1; and 0.142 L, 0.165 L and
0.172 L respectively on Day 28).
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All GW642444M doses significantly improved morning and evening PEF compared
with placebo, though the greatest improvements in morning and evening PEF over
Days 1-28 were recorded for subjects receiving 25 g GW642444M (36.2 L/min and
33.6 L/min in AM and PM PEF, respectively) and 50 g GW642444M (42.1 L/min
and 38.0 L/min in AM and PM PEF, respectively). Evening (trough) PEF
measurements further supported a sustained duration of bronchodilatory action.
The proportion of subjects obtaining 200 mL and 12% increase from baseline in
FEV1 (0-4 h) on Days 1 and 28 increased with GW642444M dose. Similar results
were found for the proportion of subjects obtaining 15% increase from baseline in
FEV1 (0-4 h) on Days 1 and 28. When expanding the time interval to 0-24 h, the
majority of subjects (>50%) in the 25 g and 50 g GW642444M groups were able
to maintain the 200 mL and 12% improvement in FEV1 for most timepoints over
this time interval.
Except for the 3 g GW642444M dose, for which no statistically significant increase
in symptom-free 24-h periods was found, all GW642444M treatments statistically
significantly increased the percentage of symptom-free and rescue-free 24 h periods
versus placebo over the 28-day treatment period. The greatest improvements were
recorded for the 25 g and 50 g GW642444M groups, with a dose-response effect
up to 25 g GW642444M for both symptom-free and rescue-free 24-h periods
(22.2% and 28.4%, respectively). No further increments were seen with 50 g
GW642444M treatment.
A dose-response was found for weighted mean change from baseline in FEV1 (0-4 h)
with all GW642444M doses showing significant improvements. The greatest
improvements versus placebo were recorded for subjects in the 25 g GW642444M
group (0.226 L on Day 1 and 0.205 L on Day 28) and the 50 g GW642444M group
(0.236 L on Day 1 and 0.213 L on Day 28). Maximum increases from baseline in 04 h FEV1 versus placebo were also greatest for the 25 g GW642444M group (0.209
L on Day 1 and 0.176 L on Day 28) and the 50 g GW642444M group (0.228 L on
Day 1 and 0.189 L on Day 28).
Analysis of the dose-response relationship for the upper and lower strata showed that
within each dose, FEV1 improved in a similar manner across the strata,
demonstrating similar dose responses for both disease severities.
Post-salbutamol/albuterol FEV1 for Day 28-Day1, Day 28-Screening, and Day 1Screening for any GW642444M dose was comparable with placebo, indicating that
tolerance to short-acting 2-agonists had not developed.
The mean change from baseline in the percentage of symptom-free days and nights
increased in a similar manner across the GW642444M groups over the 28-day
treatment period. A dose-response effect up to 25 g GW642444M was observed
with increases versus placebo in symptom-free days and nights of up to 20.3% and
17.1%, respectively. No further increments were seen with 50 g GW642444M
treatment. Results for the percentage of rescue-free days and nights over the
treatment period were similar to those observed for symptom-free days and nights.
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8.
SAFETY RESULTS
8.1.
Extent of Exposure
A summary of exposure to placebo and GW642444M administered via the Novel Dry
Powder Inhaler for the ITT Population is provided in Table 27. A total of 102 subjects
were exposed to placebo and 505 subjects were exposed across the five dosages of
GW642444M. Mean exposure to study medication was similar across the GW642444M
and placebo treatment groups. The mean exposure ranged from 25.5 days in the placebo
group to 27.6 days in the 50 g GW642444M group.
The majority of subjects were treated for 29 days (51% to 65% of subjects across
treatment groups), with a maximum of 36 days. As shown in Listing 8.1 (Attachment 5),
across the treatment groups, 13 subjects were exposed for 31 days, of whom 3 received a
replacement inhaler. The subjects who took 6.25 g GW642444M for 35 days (1
subject) and 12.5 g GW642444M for 36 days (1 subject) both received replacement
inhalers whilst one subject who took 25 g GW642444M for 32 days did not receive a
replacement inhaler.
Table 27
3 g
GW642444
N=101
6.25 g
GW642444
N=101
(days)a
12.5 g
GW642444
N=100
25 g
GW642444
N=101
50 g
GW642444
N=102
Exposure
n
102
101
101
100
101
102
Mean
25.5
25.7
26.6
26.8
27.0
27.6
SD
7.06
7.03
5.92
5.96
5.17
4.08
Median
29.0
29.0
29.0
29.0
29.0
29.0
Min-Max
1-31
1-31
4-35
1-36
5-32
6-31
Range of exposure
n
102
101
101
100
101
102
8
(8)
5
(5)
4
(4)
2
(2)
3
(3)
1
(<1)
7 days, n(%)
8-14 days, n(%)
4 (4)
8 (8)
4 (4)
6 (6)
2 (2)
3 (3)
15-28 days, n(%)
38 (37)
30 (30)
33 (33)
27 (27)
39 (39)
35 (34)
52 (51)
58 (57)
60 (59)
65 (65)
57 (56)
63 (62)
29 days, n(%)
Source data: Table 8.1.
a. Exposure was calculated as [date of last dose date of first dose] +1.
Study drug was taken for a maximum of 36 days.
For subjects who withdrew prior to Day 7 and did not have a date of last dose, the date of withdrawal was used as the
last dose date.
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8.2.
Adverse Events
An overview of AEs for the ITT Population is presented in Table 28. The incidence of
AEs on-treatment was similar across the GW642444M groups and was comparable with
placebo; this was also found for post-treatment AEs.
The incidence of AEs having a reasonable possibility of being drug-related was also
comparable between the GW642444M groups and placebo (4%-8% versus 7%,
respectively). Few AEs led to withdrawal from the study (0%-2%).
As outlined in Section 8.4 and Section 14, of the six subjects who had AEs leading to
withdrawal from the study, 2 subjects were withdrawn due to AEs and 4 subjects were
withdrawn from the study primarily due to protocol-defined stopping criteria, with related
AEs as a sub reason.
Table 28
n (%)
3 g
GW642444
N=101
37 (37)
4 (4)
8 (8)
1 (<1)
N=102
Any on-treatment AE
37(36)
Any post-treatment AE
6 (6)
Any drug-related AE
7 (7)
Any AE leading to
1 (<1)
permanent discontinuation
of drug or withdrawala
Source data: Table 8.2, Table 8.3, Table 8.5, Table 8.6.
a.
8.2.1.
6.25 g
GW642444
N=101
34 (34)
5 (5)
8 (8)
2 (2)
12.5 g
GW642444
N=100
25 (25)
0
5 (5)
1 (1)
25 g
GW642444
N=101
23 (23)
5 (5)
4 (4)
1 (<1)
50 g
GW642444
N=102
31 (30)
2 (2)
7 (7)
0
AEs reported during the treatment period are presented in Table 8.2. The incidence of
on-treatment AEs was highest in the placebo, 3 g GW642444M and 6.25 g
GW642444M groups (34%-37%). The most commonly reported AEs occurred in the
nervous system disorders (8-14% of subjects across treatment groups including placebo)
and infections and infestations (3-12% of subjects across treatment groups including
placebo) categories.
A summary of the most frequent on-treatment AEs is presented in Table 29. Headache
was the most commonly observed AE in all groups and was comparable to placebo.
Other AEs included upper respiratory tract infection, nasopharyngitis, dizziness, back
pain, muscle spasms and dyspnoea.
The incidence of AEs potentially reflecting LABA class effects (such as tremor,
palpitations, glucose and potassium effects) was low.
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The incidence of AEs in Cardiac disorders category, including palpitations, was low and
similar between treatment arms and placebo.
8.2.2.
Placebo
N=102
37 (36)
8 (8)
2 (2)
3 g
GW642444
N=101
37 (37)
12 (12)
2 (2)
6.25 g
GW642444
N=101
34 (34)
7 (7)
1 (<1)
12.5 g
GW642444
N=100
25 (25)
9 (9)
3 (3)
25 g
GW642444
N=101
23 (23)
7 (7)
2 (2)
50 g
GW642444
N=102
31 (30)
8 (8)
2 (2)
4 (4)
2 (2)
0
0
3 (3)
2 (2)
1 (<1)
3 (3)
0
0
2 (2)
1 (<1)
0
2 (2)
0
0
1 (1)
1 (1)
0
0
0
0
1 (<1)
0
0
2 (2)
3 (3)
0
3 (3)
0
AEs reported for the ITT population during the post-treatment period are presented in
Table 8.3. The incidence of post-treatment AEs was similar across all treatment groups
(2%-6%) although no AEs were recorded for the 12.5 g GW642444M group following
treatment. The most frequently reported post-treatment AE was headache (2% in any
treatment group), followed by bronchitis, nasopharyngitis, upper respiratory tract
infection and pharyngolaryngeal pain (all <1% in any treatment group).
8.2.3.
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8.3.
Placebo
N=102
7 (7)
3 g
GW642444
N=101
8 (8)
6.25 g
GW642444
N=101
8 (8)
12.5 g
GW642444
N=100
5 (5)
25 g
GW642444
N=101
4 (4)
50 g
GW642444
N=102
7 (7)
0
0
0
2 (2)
1 (<1)
1 (<1)
3 (3)
2 (2)
0
2 (2)
2 (2)
0
2 (2)
2 (2)
0
2 (2)
0
2 (2)
2 (2)
1 (<1)
2 (2)
2 (2)
1 (<1)
1 (<1)
1 (1)
0
1 (<1)
0
0
0
8.4.
In total, 6 subjects were withdrawn from the study due to AEs, with no more than 2
subjects withdrawing in any treatment group and no subjects withdrawing in the 50 g
GW642444M group (Table 31). In 2 subjects withdrawal due to AE was quoted as the
primary reason, and for the remaining 4 subjects the primary reason for withdrawal from
the study was subject reaching protocol-defined stopping criteria, with related AEs as a
sub reason for withdrawal. Detailed information is provided in Section 14 (Case
Narratives).
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Table 31
Placebo
3 g
GW642444
N=101
1 (<1)
N=102
Any event
1 (<1)
Cardiac disorders
Any event
1 (<1)
0
AV block second degree
0
0
Ventricular arrhythmia
1 (<1)
0
General disorders and administration site conditions
Any event
0
1 (<1)
Feeling jittery
0
1 (<1)
Pyrexia
0
0
Investigations
Any event
0
0
ECG PR prolongation
0
0
ECG T wave amplitude
0
0
decreased
Immune system disorders
Any event
0
0
Hypersensitivity
0
0
Nervous system disorders
Any event
0
1 (<1)
Psychomotor hyperactivity
0
1 (<1)
Psychiatric disorders
Any event
0
1 (<1)
Insomnia
0
1 (<1)
Source data: Table 8.6.
6.25 g
GW642444
N=101
2 (2)
12.5 g
GW642444
N=100
1 (1)
25 g
GW642444
N=101
1 (<1)
50 g
GW642444
N=102
0
0
0
0
1 (1)
1 (1)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1)
0
1 (<1)
0
0
0
2 (2)
1 (<1)
1 (<1)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1)
1 (<1)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
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8.5.
8.5.1.
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Summaries of chemistry and haematology data including changes from baseline are
presented in Table 8.11 to Table 8.16.
Mean and median values at Days 14 and 28 of the study period were similar, with no
changes for haematology analytes and clinical chemistry analytes below predefined levels
of clinically relevant concern.
Urinalysis dipstick results are provided in Table 8.17. At Screening and Day 28, results
were similar across the treatment groups for all urinalysis parameters (glucose, ketones,
WBCs, protein, pH and specific gravity).
8.5.2.
8.5.2.1.
The percentages of clinical chemistry values outside the normal range were generally
similar across treatment groups including placebo, across all analytes and throughout the
duration of the study (Screening, Days 14 and 28 and any Visit post-Screening)
(Table 8.12).
Small increases in the incidence of values outside the normal range for creatine
phosphokinase (CPK) were observed with active treatment arms combined (19.6%)
compared to placebo (10.7%). Most values were below twice the upper limit and no dose
response was observed. Six subjects (1.2 %) in the active arms combined compared to 0
subjects in placebo had CPK values above five times the upper limit (Listing 8.10,
Attachment 5). No more than 26% of subjects in any treatment group at any of the time
points reported analyte values outside the normal range (Table 8.12). Similar results
were found for the percentages of haematological values outside the normal range, with a
minor overall decrease in haematocrit, haemoglobin and red blood cell count across all
treatment groups with time (Table 8.15).
Clinical chemistry changes from baseline relative to the normal range by time point (Day
14 and Day 28) were classified as shifting to low, shifting to normal or no change, or
shifting to high. Analysis showed that for all clinical chemistry analytes, 86% or more
subjects in any treatment group had no change or experienced shifts into the normal range
during the treatment period (Table 8.13). For haematology this was 76% (Table 8.16).
Potassium and Glucose
Up to 2% and 11% of subjects in any treatment group at any of the pre-dose time points
recorded low potassium and high glucose levels outside the normal range, respectively
(Table 8.12 and Table 8.15). Overall, for potassium and glucose, maximum changes
from baseline and weighted mean changes from baseline (0-4 h), including changes
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versus placebo, did not exceed the predefined levels of clinically relevant concern (see
Section 8.6.3).
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Figure 19
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8.5.2.2.
Liver Function
A box plot of maximum post-baseline liver function test (LFT) results is presented in
Figure 8.2. Maximum post-baseline LFT values were similar across the GW642444M
treatment groups and comparable to placebo.
This event was deemed related to
study drug (Listing 8.10, Attachment 5). Bilirubin and alkaline phosphatase levels were
within normal range. This subject had recovered at the time of Database closure.
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8.6.
8.6.1.
Vital signs
8.6.1.1.
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Throughout the treatment period, mean maximum increases in systolic blood pressure
over 0-4 h after dosing were similar across the treatment groups including placebo and
ranged from 2.9 mmHg to 7.0 mmHg versus baseline (Table 8.20). Statistical analysis
showed that differences with placebo for maximum increase in systolic blood pressure
were not significant for any group throughout the treatment period (Table 8.22).
Summaries of weighted mean change from baseline and pre-dose in systolic blood
pressure (0-4 h) are presented in Table 8.29 and Table 8.30, respectively. There was no
evidence of a statistically significant difference in weighted mean change from baseline
with placebo for any group at any time point (Table 8.31).
8.6.1.2.
Throughout the treatment period, mean maximum decreases (i.e., change from baseline in
minimum value) in diastolic blood pressure 0-4 h after dosing were similar across the
treatment groups including placebo and ranged from -2.5 mmHg to -6.6 mmHg versus
baseline (Table 8.23). Statistical analysis showed that differences with placebo for
maximum decrease in diastolic blood pressure were only significant for the 50 g
GW642444M group on Day 1 (-2.5 mmHg, p=0.004), and for the 6.25 g GW642444M
group on Day 14 (-2.1 mmHg, p=0.049) (Table 8.25).
Summaries of weighted mean change from baseline and pre-dose in diastolic blood
pressure (0-4 h) are presented in Table 8.32 and Table 8.33, respectively. Except for the
50 g GW642444M group on Day 1, there was no evidence of a statistically significant
difference in weighted mean change from baseline versus placebo 0-4 h after dosing for
any group at any time point (Table 8.34). For the 50 g GW642444M group, the
decrease in weighted mean diastolic blood pressure of -1.7 mmHg versus placebo on Day
1 was statistically significant (p=0.030), but unlikely to be of clinical relevance.
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8.6.1.3.
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Pulse Rate
Throughout the treatment period, mean maximum increases in pulse rate over 0-4 h after
dosing were similar across the treatment groups including placebo and ranged from 1.1
bpm to 7.1 bpm versus baseline (Table 8.26). Statistical analysis showed that differences
from placebo for maximum increases from baseline in pulse rate were significant for the
12.5 g group on Day 1 (-1.9 bpm, p=0.035) and for the 50 g GW642444M group on
Day 28 (2.7 bpm, p=0.026) (Table 8.28). However, a difference of 2.7 bpm was below
predefined levels of clinically relevant concern (6 bpm).
Summaries of weighted mean change from baseline and pre-dose in pulse rate (0-4 h) are
presented in Table 8.35 and Table 8.36, respectively. Except for the 50 g GW642444M
group on Day 28, there was no evidence of a statistically significant difference in
weighted mean change versus placebo 0-4 h after dosing for any group at any time point
(Table 8.37). For the 50 g GW642444M group, the increase in weighted mean pulse
rate of 2.2 bpm versus placebo on Day 28 was statistically significant (p=0.047) but
below predefined levels of clinically relevant concern.
8.6.2.
Twelve-Lead ECG
A summary of ECG values (heart rate, uncorrected QT interval, QTc(F) and QTc(B), PR
interval and QRS duration) on Days 1, 7, 14 and 28 is provided in Table 8.38.
Abnormal and clinically significant ECG findings over time as assessed by the
independent cardiologist are summarised in Table 8.39. At any time post-baseline, the
incidence of absolute clinically significant abnormal ECG findings was similar across the
GW642444M treatment groups (6% to 12% of subjects) and comparable to placebo (8%)
(Table 32).
A summary of ECG changes at any time post-baseline Table 33 shows that the incidence
of unfavourable clinically significant changes was similar across the GW642444M
treatment groups (17%-19%) and comparable with placebo (18%). Of note is that not all
the changes listed in Table 33 are considered to be a clinically significant abnormality: a
subject can have a clinically significant change at the same time s/he has a normal result;
Table 32 and Table 33 therefore do not correlate exactly.
As outlined in Section 8.4 and Section 14 (case narratives), 4 subjects were withdrawn
due to ECG protocol-defined stopping criteria: one subject receiving placebo (ventricular
tachycardia), two subjects receiving 6.25 g GW642444M (T-wave amplitude decreased
and PR prolongation), and one subject receiving 12.5 g GW642444M (AV block second
degree).
In general, a greater incidence of subjects with an absolute maximum post-dose QTc
prolongation >450 msec across all treatment groups and over time was found when QTc
was calculated using Bazett's formula (incidence of up to 11%) than if corrected using
Fridericia's formula (incidence of up to 5%) (Table 8.40 and Table 8.41). For both QTc(F)
and QTc(B) no dose response was found across the treatment groups on any of the days
studied, including no clinically relevant difference to placebo.
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Whilst no maximum post-dose QTc(F) intervals of >500 msec were recorded at any time
point (Table 8.40), two subjects recorded post-dose QTc(B) intervals of >500 msec
(Table 8.41 and Listing 8.14, Attachment 5).
Table 32
n (%)
3 g
GW642444
N=101
101
38 (38)
51 (50)
6.25 g
GW642444
N=101
101
41 (41)
54 (53)
12.5 g
GW642444
N=100
100
50 (50)
40 (40)
25 g
GW642444
N=101
101
42 (42)
47 (47)
N
Normal
Abnormal - not clinically
significant
Abnormal clinically
8 (8)
12 (12)
6 (6)
10 (10)
12 (12)
significant
Not available
0
0
0
0
0
Source data: Table 8.39.
Abnormality and clinical significance determined by the central cardiologist.
A subject can have a clinically significant change at the same time s/he has a normal result
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50 g
GW642444
N=102
102
50 (49)
45 (44)
7 (7)
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Table 33
n (%)
Placebo
3 g
GW642444
N=101
101
0
6.25 g
GW642444
N=101
101
0
12.5 g
GW642444
N=100
100
0
25 g
GW642444
N=101
101
0
50 g
GW642444
N=102
102
0
N=102
N
102
Clinically significant
1 (<1)
change: favourable
Clinically significant
18 (18)
19 (19)
17 (17)
17 (17)
18 (18)
17 (17)
change: unfavourable
No change or insignificant
77 (75)
79 (78)
80 (79)
81 (81)
76 (75)
82 (80)
change
No result
6 (6)
3 (3)
4 (4)
2 (2)
7 (7)
3 (3)
Source data: Table 8.39.
Abnormality and clinical significance determined by the central cardiologist.
A subject can have a clinically significant change at the same time s/he has a normal result.
This table does not correlate exactly with Table 32 since not all the changes listed in Table 33 are considered to be a
clinically significant abnormality: a subject can have a clinically significant change at the same time s/he has a normal
result. Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
8.6.2.1.
Heart rate
QTc(F)
Summaries of weighted mean change from baseline and pre-dose (0-4 h) in QTc(F)
interval are provided in Table 8.44 and Table 8.45, respectively. No statistically
significantly weighted mean change from baseline (0-4 h) in QTc(F) interval was reported
for any treatment comparison to placebo, at the study Days 1, 7, 14 and 28 (Table 8.52).
Change from Baseline 0-4 hours Post-Dose Serial QTc(F)
In contrast to the analysis of weighted mean change, the analysis of serial QTc(F)
measured at 10 minutes, 1, 2 and 4 h following dosing on Days 1, 7, 14 and 28 showed a
statistically significant difference in mean post-dose serial QTc(F) (0-4 h) change from
baseline for 50 g GW642444M compared with placebo. Ten minutes after dosing on
Day 1, subjects in the 50 g GW642444M group recorded a statistically significant
difference in mean QTc(F) increase from baseline versus placebo of 4.1 msec (p=0.030)
(Table 8.48). In addition, 10 minutes after dosing on Day 7, subjects in the 50 g
GW642444M group recorded a statistically significant difference in mean QTc(F) increase
from baseline versus placebo of 5.0 msec (p=0.035). A predefined level of clinical
concern for changes in QTc for this study was agreed at 5 msec based on FDA
Guidance for Industry for clinical evaluation of QT/QTc prolongation [FDA Guidance
for Industry, 2005].
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In addition, a statistically significant decrease in QTc(F) versus placebo was found for the
6.25 g group 4 h after dosing on Day 14 (-5.9 msec, p=0.014). At other time points, any
changes in QTc(F) versus placebo did not reach statistical significance in any treatment
group.
The adjusted treatment differences from placebo for serial QTc(F) on Days 1, 7, 14 and 28
are shown in Figure 20.
Figure 20
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GW642444M groups were comparable to placebo (Table 8.42 and Figure 8.4). Across
the study days, only 2 or fewer subjects (2%) in the 3 g, 6.25 g, 12.5 g and 25 g
GW642444M groups had maximum changes from baseline in QTc(F) (0-4 h) of 60 msec
(Table 8.42). No subjects in the placebo and 50 g GW642444M groups recorded
maximum changes from baseline 60 msec.
Although up to 17% of subjects in any treatment group at any time point were reported to
have high maximum increases in QTc(F) (0-4 h), statistical analysis showed that any
differences with placebo 0-4 h after dosing were not statistically significant for any group
throughout the treatment period (Table 8.50).
8.6.2.3.
QTc(B)
Summaries of weighted mean change from baseline and pre-dose (0-4 h) in QTc(B)
interval are provided in Table 8.46 and Table 8.47, respectively.
Statistical analysis showed that there was evidence of an increase in QTc(B) interval
compared with placebo only on 50 g GW642444M treatment (Day 1, 4 msec increase
(p=0.034) (Table 8.53). However, this value was below the pre-defined threshold of
clinical concern.
There were no statistically significant treatment differences in weighted mean change
from baseline (0-4 h) in QTc(B) interval for any other treatments on any day (Table 8.53).
Change from Baseline 0-4 hours Post-Dose Serial QTc(B)
Analysis of change from baseline in post-dose serial QTc(B) showed that on several
occasions following dosing on all study Days, treatment with 6.25 g, 25 g and 50 g
GW642444M resulted in statistically significant increases versus placebo in post-dose
serial QTc(B) (Table 8.49). Adjusted treatment differences of change from baseline in
post-dose serial QTc(B) are depicted graphically in Figure 8.9.
Most of the statistically significant increases in post-dose serial QTc(B) were recorded for
the 50 g GW642444M group: on seven occasions, 10 minutes to 1 h post-dose on all
study Days, the 50 g GW642444M group had mean treatment differences greater than 5
msec (6 msec 12.5 msec) following dosing. Statistically significant treatment
differences greater than 5 msec were also found for the 25 g GW642444M group (6.1
msec at 10 minutes on Day 1 and 8.2 msec at 1 h on Day 14). As mentioned in
Section 8.6.2.2, a predefined level of clinical concern for changes in QTc for this study
was agreed at 5 msec based on FDA Guidance for Industry for clinical evaluation of
QT/QTc prolongation [FDA Guidance for Industry, 2005].
In addition, there was a statistically significant QTc(B) treatment difference of 4.9 msec
recorded for the 6.25 g GW642444M group on Day 1 at 10 minutes.
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Scatter plots of serial QTc(F) and QTc(B) versus heart rate on Days 1, 7, 14 and 28 are
presented in Figure 8.10 and Figure 8.11. For QTc(F) and heart rate, there was no strong
evidence of an association between these parameters on any of the time points suggesting
QTc(F) values are independent of heart rate . The scatter plot of QTc(B) and heart rate
showed positive correlation for for QTc(B) versus heart rate, which suggests that QTc(B)
does not completely correct for heart rate at the extremes. This is in line with the known
observation that QTc(B) over-corrects at high heart rates and under-corrects at low heart
rates [FDA Guidance for Industry, 2005]. Consequently data corrected as QTc(F)was
considered to be the most relevant and accurate for this review.
8.6.3.
Summary statistics of fasting potassium and glucose on Days 1 and 28 and non-fasting
potassium on Days 7 and 14 only are provided in Table 8.54 and Table 8.55. Changes
from baseline relative to the normal range (shift tables) are presented in Table 8.56 and
Table 8.57.
Changes from baseline relative to the normal range were classified as shifting to low,
shifting to normal or no change, or shifting to high; with the levels of clinical concern set
at a difference of -0.3 mmol/L and 1.5 mmol/L versus placebo for potassium and glucose,
respectively.
8.6.3.1.
Potassium
For fasting potassium, 81% or more subjects in any treatment group had no change or
experienced shifts into the normal range during the treatment period (Table 8.56). For
non-fasting potassium this was 83% (Table 8.57).
Mean potassium treatment differences from placebo did not go below the 0.3 mmol/L
predefined level of clinically relevant concern. Several subjects recorded values of >7
mmol/L; individual profiles for these subjects and discussion are presented in Attachment
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2. Outlying values of >7 mmol/L were thought by Quest Laboratories and GSK to be due
to non-usable samples.
Fasting Potassium - Maximum Decrease from Baseline and from Pre-Dose (0-4
hours)
Summaries of maximum decrease from baseline and pre-dose in fasting potassium (0-4 h)
are provided in Table 8.58 and Table 8.59, respectively. Statistical analysis (Table 8.70)
showed that on Day 28, decreases of -0.14 mmol/L from baseline versus placebo for both
the 6.25 g and 50 g GW642444M groups were statistically significant. However,
these changes were below predefined levels of clinically relevant concern
Fasting Potassium - Weighted Mean Change from Baseline and from Pre-Dose (0-4
hours)
Summaries of weighted mean change from baseline and pre-dose in fasting potassium (04 h) are provided in Table 8.64 and Table 8.65, respectively. Apart from a statistically
significant weighted mean decrease in fasting potassium of -0.130 mmol/L versus
placebo in the 50 g GW642444M group on Day 1, which was below predefined levels
of clinically relevant concern, no weighted mean changes from baseline in any treatment
group at Day 1 or Day 28 reached statistical significance (Table 8.73).
Non-Fasting Potassium - Maximum Decrease from Baseline and from Pre-Dose (04 hours)
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Glucose
For glucose, 78% or more subjects in any treatment group had no change or experienced
shifts into the normal range during the treatment period (Table 8.56). Mean treatment
differences from placebo did not go above the predefined level of clinically relevant
concern (1.5 mmol/L).
Maximum Increase from Baseline and from Pre-Dose in Glucose (0-4 hours)
Summaries of maximum increase from baseline and pre-dose in glucose (0-4 h) are
provided in Table 8.62 and Table 8.63, respectively. Statistical analysis showed that,
except for the 6.25 g GW642444M group on Day 1, maximum changes in glucose
versus placebo in any treatment group at any time point were not statistically significant
(Table 8.72). A statistically significant change versus placebo of -0.25 mmol/L in the
6.25 g GW642444M group on Day 1 (p=0.044) did not exceed predefined levels of
clinically relevant concern.
Weighted Mean Change from Baseline and from Pre-Dose in Glucose (0-4 hours)
Summaries of weighted mean change from baseline and pre-dose in glucose (0-4 h) are
provided in Table 8.68 and Table 8.69, respectively. Apart from a statistically significant
weighted mean change in glucose of -0.185 mmol/L versus placebo in the 6.25 g
GW642444M group on Day 1, which did not exceed predefined levels of clinically
relevant concern, no weighted mean changes from baseline in any treatment group at Day
1 or Day 28 reached statistical significance (Table 8.75).
8.6.4.
Asthma Exacerbations
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Table 34
n(%)
Placebo
8.6.5.
N=102
4 (4)
1 (<1)
3 g
GW642444
N=101
7 (7)
3 (3)
6.25 g
GW642444
N=101
2 (2)
2 (2)
12.5 g
GW642444
N=100
0
0
25 g
GW642444
N=101
3 (3)
1 (<1)
50 g
GW642444
N=102
1 (<1)
0
1 (<1)
2 (2)
2 (2)
5 (5)
1 (<1)
2 (2)
0
0
0
1 (<1)
0
0
2 (2)
2 (2)
2 (2)
1 (<1)
0
0
0
0
1 (<1)
0
1 (<1)
0
0
0
1 (<1)
1 (<1)
0
2 (2)
0
3 (3)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1)
1 (<1)
0
0
0
0
0
0
0
0
0
0
0
1 (<1)
0
0
0
0
0
1 (<1)
0
0
0
0
1 (<1)
0
0
0
0
1 (<1)
1 (<1)
1 (<1)
0
0
0
0
0
0
0
0
1 (<1)
0
0
0
0
0
0
0
0
No incidents, near incidents or malfunctions were reported with the use of the medical
device(s) manufactured or marketed by GSK or by a third party for GSK, for this study.
Five malfunctions were reported for the Novel Dry Powder Inhaler (1 malfunction in
each of the placebo, 3 g, 6.25 g, 25 g and 50 g GW642444M groups), which were
mainly due to mechanical reasons (Listing 8.18, Attachment 5).
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8.7.
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Safety Summary
Throughout the 28-day treatment period, GW642444M was well tolerated at all
doses. The overall incidence of AEs was similar across the GW642444M treatment
groups (ranging from 23% to 37%) and was comparable to placebo. Headache was
the most common AE in all treatment groups including placebo and occurred at an
incidence of 7-12%. Other, commonly reported AEs included upper respiratory tract
infection, nasopharyngitis and dizziness. There was no dose-related increase in the
frequency of the most commonly reported AEs across the GW642444M doses.
In total, 6 subjects (0%-2% across treatment groups, with no more than 2 subjects
per group) were withdrawn from the study due to AEs though in only two cases was
the AE the primary reason for the withdrawal. One subject was withdrawn due to
the AE of psychomotor hyperactivity, feeling jittery and insomnia (3 g
GW642444M) and another subject was withdrawn due to an increase in allergy
symptoms and pyrexia (25 g GW642444M). The other 4 subjects were withdrawn
due to protocol stopping criteria with related AEs as a sub reason.
Maximum post-baseline liver function tests were similar across the GW642444M
treatment groups and comparable to placebo.
For potassium, maximum decreases from baseline and weighted mean changes from
baseline (0-4 h), including changes versus placebo, did not exceed the predefined
levels of clinically relevant concern. No AEs of hypokalaemia were reported.
For glucose, maximum increases from baseline and weighted mean change from
baseline (0-4 h), including changes versus placebo, mean treatment differences from
placebo did not exceed the predefined levels of clinical concern.
No safety concerns were noted from the results of vital signs assessments. For pulse
rate and systolic and diastolic blood pressure, no treatment-related changes were
apparent and differences from baseline versus placebo were deemed not clinically
significant.
Any statistically significant increases from baseline versus placebo in serial QTc(F)
(0-4 h) were deemed not clinically relevant. There were no statistically or clinically
significant treatment differences in weighted mean or maximum change from
baseline (0-4 h) in QTc(F) for any treatment group, at any time point.
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In contrast, statistically significant changes from baseline in serial QTc(B) of >5 msec
10 minutes to 1 h following dosing on all study days in the 50 g GW642444M
group were recorded. Treatment differences >5 msec were also found for the 25 g
GW642444M group on Day 1 at 10 minutes post-baseline and Day 14 at 10 minutes
and 1 h post-baseline. However, the plots of QTc(B) versus heart rate suggest that
QTc(B tends to under-correct at low and over-correct at high heart rate.
No safety concerns were raised for heart rate values measured by ECG.
The incidence of asthma exacerbations was low and similar across the treatment
groups, with the highest percentage of events in the placebo and 3 g GW642444M
groups (4% to 7%, respectively), compared with 0% to 3% in the other groups.
9.
BIOANALYTICAL RESULTS
Quality Control (QC) samples for the analysis of GW642444, GW630200, GSK932009
and triphenylacetate counter-ion, prepared at three different analyte concentrations and
stored with study samples, were analysed with each batch of samples against separately
prepared calibration standards. For the analysis to be acceptable, no more than one-third
of the QC results and no more than one-half of the results from each concentration level
were to deviate from the nominal concentration by more than 15%. All applicable
analytical runs met all predefined run acceptance criteria.
10.
PHARMACOKINETIC RESULTS
10.1.
10.1.1.
GW642444
The percentage (%) of samples analysed for GW642444 which were below the Lower
Limit of Quantification (LLQ 30 pg/mL) are summarised by pharmacokinetic sample
collection time window, visit and treatment in Table 35.
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Table 35
Visit
(Day +4/-2)
3 g
GW642444
2 (Day 1)
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
3 (Day 7)
Pre-dose
4 (Day 14)
2 min -1 h
5 (Day 28)
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Source data: Table 9.1
10.1.1.1.
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100
97
99
100
100
100
90
99
88
94
99
100
6.25 g
12.5 g
25 g
GW642444
GW642444
GW642444
Total (%) sample below LLQ (30 pg/mL)
99
97
98
84
48
21
93
67
41
97
92
79
98
96
94
99
98
97
63
37
26
99
96
93
57
20
10
88
44
20
100
90
48
100
95
78
50 g
GW642444
99
13
10
20
58
89
23
92
10
3
3
18
3g GW642444M
Plasma concentrations of GW642444 were below the LLQ (30 pg/mL) in the majority
(88%) of samples analysed from subjects who received single and repeat doses of 3g
GW642444M. A minority of subjects had quantifiable plasma concentrations of
GW642444 which were generally observed at a single time point within 10 min of dosing
at concentrations just above the LLQ (30-45pg/mL; Figure 9.1). Plasma concentrations
( 90 pg/mL) were reported in 3 subjects. Higher levels (165 and 201 pg/mL) were
observed in 2 subjects approximately 0.5 h after dosing. Median concentrations (by PK
sample collection period) were below LLQ (Attachment 3). Based on the high % NQ
concentrations across all timepoints and visits (97%), the data were considered too
limited for nonlinear mixed effects modelling.
10.1.1.2.
6.25g GW642444M
GW642444 was quantifiable in 16% of the samples analysed from subjects following a
single dose and 43% of samples analysed after repeat (28 days) dosing with 6.25 g
GW642444M. Generally GW642444 was only quantifiable at a single time point within
15 min post-dose. A minority of asthmatics had quantifiable concentrations of
GW642444 in 2 consecutive post-dose samples and a single individual had quantifiable
concentrations up to 4 h post-dose on Day 1 (Visit 2) of the study.
Median concentrations (by PK sample collection period) were below LLQ (see
Attachment 3). Based on the high % NQ concentrations across all timepoints and visits
(90%; Table 35), the data were considered too limited for nonlinear mixed effects
modelling.
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10.1.1.3.
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12.5g GW642444M
GW642444 was quantifiable in 52% of the subjects after a single dose and 80% of
subjects following repeated administration (28 days) of 12.5 g GW642444M. However,
plasma concentration-time profiles were very limited (Figure 9.1) with 2 quantifiable
post-dose concentrations/individual/day. Plasma concentrations fell below the LLQ in the
majority of samples collected beyond 30 min post-dose (Table 35). Median
concentrations (by PK sample collection period) were just above the LLQ in early (0-30
min) time collection periods (Attachment 3). Based on the high % NQ values (74%;
Table 35) across all timepoints and visits, the data were considered too limited for
nonlinear mixed effects modelling.
10.1.1.4.
25g GW642444M
GW642444 was quantifiable in plasma of the majority of the subjects who received
single and repeat doses of 25 g GW642444M. Again profiles were limited; generally
2 quantifiable post-dose concentrations/individual/day. In majority of subjects plasma
concentrations of GW642444 fell below the LLQ beyond 30 min post-dose after a single
and 2 h following repeat (28 days) inhaled administration (Table 33). Maximum
observed concentrations were generally seen within 30 min post-dose and ranged from
30-328 pg/mL (Figure 9.1). Median concentrations (by PK sample collection period)
were above LLQ in early (0-30 mins) time collection periods (Attachment 3). Based on
the high % NQ concentrations across all timepoints and visits (59%; Table 35), the data
were considered too limited for nonlinear mixed effects modelling.
10.1.1.5.
50g GW642444M
GW642444 was quantifiable in plasma of the majority of the asthmatic patients who
received single and repeat doses of 50 g GW642444M. Profiles were still relatively
limited. Across all timepoints and visits 37% of the samples analysed for GW642444
were NQ. GW642444 was quantifiable in the majority (80%) of samples collected up to
2 h post-dose on Day 1, thereafter ( 2h post-dose) the majority of samples (58%) were
NQ. On Day 28 profiles were more extensive; 82% of samples collected up to 4 h postadministration on Day 28 had quantifiable levels of GW642444. Maximum observed
concentrations were generally seen within 30 min post-dose and ranged from 30-975
pg/mL (Figure 9.1). Median concentrations (by PK sample collection period) were 250
pg/mL (Attachment 3). Plasma GW642444 concentration-time data following 50 g
GW642444M were subjected to nonlinear mixed effects modelling.
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10.1.2.
Table 36
Visit
(Day +4/-2)
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Triphenylacetate (counterion)
Triphenylacetate: Summary of % of NQ values by treatment, Day and
Time
Time
Window
2 (Day 1)
Pre-dose
2-10 min
10-30 min
30 min 2h
2-4 h
3 (Day 7)
Pre-dose
4 (Day 14)
2min -1 h
5 (Day 28)
Pre-dose
2-10 min
10-30 min
30 min 2h
2-4 h
Source data: Table 9.1
3 g
GW642444
100
100
100
99
100
100
99
100
100
99
100
100
6.25 g
12.5 g
25 g
GW642444
GW642444
GW642444
Total (%) sample below LLQ (1ng/mL)
100
100
100
100
100
100
99
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
99
99
100
99
100
100
100
99
100
99
100
100
50 g
GW642444
100
98
100
100
99
100
99
100
95
100
99
98
GW630200
GW630200 was not quantifiable (LLQ 90 pg/mL) in any subject following 3, 6.25, 12.5,
25 or 50 g GW642444M (Table 9.1) The metabolite was only quantified in plasma
(191 pg/mL) in a single subject (approximately 0.2% of total population to receive active
treatment) 10 min post-administration of 12.5 g GW642444M on Visit 4 of the study
(Day 14).
10.1.4.
GSK932009
The metabolite, GW630209 was not quantifiable (LLQ 180 pg/mL) in plasma of any
subject following 3, 6.25, 12.5 or 25 g GW642444M (Table 9.1). A single subject
(approximately 0.2% of total population to receive active treatment) had quantifiable
concentrations (268-476 pg/mL) pre-dose and up to 4 h post-dose at Visit 5 following 50
g GW642444M. This subject had the highest GW642444 concentrations reported in the
study.
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10.2.
10.2.1.
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Noncompartmental Analysis
10.2.2.1.
GW642444 Cmax
An estimate of Cmax and tmax was obtained directly from the raw concentration-time
data collected over the period 2-30 minutes post-dose on days 1 and 28 (across 2-10 min
and 10-30 min samples). If tmax was outside this window, tmax and Cmax were
reported as not determined (ND) and set to missing. Across all doses 8% of tmax
values were outside the 2-30 min window. Observed Cmax and tmax are summarised by
dose and visit in Table 37.
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Table 37
Parameter
(units)
Cmax (pg/mL)
Tmax (h)
Visit
N*
95% CI
Median
Range
96
69
Geometric
mean
NA
NA
2
5
100
82
100
82
NA
NA
NC
NC
NC - 165.6
NC - 201.6
6.25
2
5
101
90
96
88
79
50
NA
NA
NA
NA
NC
NC
NC 121.7
NC - 170.0
12.5
2
5
100
89
97
86
40
14
NA
NA
NA
NA
41.0
59.9
NC - 215.1
NC 200.3
25
2
5
101
92
98
91
17
8
59.3
96.5
50.5 - 69.7
82.4 113.1
64.8
119.6
NC - 260.7
NC - 328.1
50
2
5
2
5
102
97
100
82
93
89
4
13
6
3
96
69
139.1
223.0
ND
ND
117.8164.1
189.6 262.4
ND
ND
142.1
267.4
0.15
0.15
NC - 623.6
NC - 975.6
0.05 - 0.48
0.05 - 0.50
6.25
2
5
101
90
17
38
79
50
ND
ND
ND
ND
0.20
0.17
0.05 - 0.42
0.05 - 0.37
12.5
2
5
100
89
57
72
40
14
ND
ND
ND
ND
0.17
0.17
0.03 - 0.45
0.03 - 0.45
25
2
5
101
92
81
83
17
8
ND
ND
ND
ND
0.17
0.17
0.03 - 0.53
0.05 - 0.47
50
2
5
102
97
87
86
6
3
ND
ND
ND
ND
0.17
0.17
0.05 0.52
0.05 - 0.48
10.2.2.2.
As observed Cmax (2-30 min post-dose) at low doses (6.25 g) was censored by LLQ
(>55% of data reported as NC), covariate effects were only investigated for 12.5 50 g
GW642444M.
There was no notable effect of patient sex or baseline FEV1 stratum ( 65%-90% or
40%-65%) on observed Cmax (Table 38). Ethnicity, race and smoking covariates were
not investigated as the majority patients at each dose of GW642444M were non-Hispanic
and had never smoked (Table 5 and Section 6.4.2.1). Similarly, 73% of patients at each
GW642444M dose were of white/Caucasian/European heritage with all other races
representing <14% of the population (Table 5). Data were also too limited to investigate
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the effect of CYP3A4 inhibitors; only five patients receiving active treatment (12.5 and
25 g) were administered a moderate inhibitor during the study.
Table 38
Visit 2 (Day1)
Males
Females
Visit 5 (Day28)
Males
Females
STRATA
Visit 2 (Day1)
Lower
(65-90)
Upper
(40-65)
Visit 5 (Day28)
Lower
(65-90)
Upper
(40-65)
12.5 g GW642444
(M44/F56)
42.6
[NC-98.8]
39.6
[NC-215.1]
12.5 g
(M37/F52)
62
[NC-200.3]
59.5
[NC-128.5]
25 g GW642444
(M40/F61)
47.5
[NC-133.3]
74.8
[NC-260.7]
25 g
(M36/F57)
98.4
[NC-325.9]
127
[NC-328.1]
50 g GW642444
(M45/F56a)
133.6
[NC-412.4]
158.1
[NC-623.6]
50 g
(M44/F53)
215.1
[NC-647.4]
287.1
[NC-975.6]
12.5 g
(M58/F42)
47.8
[NC-215.1]
NC
[NC-98.8]
12.5 g
(M53/F36)
62.7
[NC-169.1]
49.5
[NC-200.3]
25 g
(M54/F47)
88.4
[NC-208.3]
44.2
[NC-260.7]
25 g
(M50/F43)
127.7
[NC-256.4]
92.3
[NC-328.1]
50 g
(M56/F45)
186.5
[NC-623.6]
131
[NC-423.4]
50 g
(M49/F40)
271.3
[NC-975.6]
266.9
[NC-471.9]
There was no clear correlation between patient age, body weight or BMI and observed
Cmax (Figure 9.2).
10.3.
Pharmacokinetic Summary
Observed Cmax (over period 2-30 min post-dose) provided an estimate of systemic
exposure to GW642444M and increased with dose and showed a tendency for higher
exposure on repeat dosing. There was no clear covariate effect on observed Cmax.
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11.
PHARMACOKINETIC/PHARMACODYAMIC RESULTS
11.1.
11.2.
All datasets were provided with the dose response modelling strategy predefined in
Section 13 of the RAP. Additional details of PK/PD analysis methodology are described
in Attachment 4
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The ITT dataset containing observed individual trough day 28 FEV1 data with patient
covariates was used for estimating the dose response model parameters (including
placebo effect and inter-patient variability, potency (ED50) and maximum predicted
effect (Emax). This analysis supplements the information provided from the primary
statistical analysis.
For modelling time course of FEV1 across all treatments, the dataset consists of all
patients who provided at least 1 profile for time course of FEV1 (Day 1 and/or Day 28)
with a minimum of at least 6 FEV1 measurements for each profile. The aim of the
analysis was to characterise the time course of FEV1 as a function of dose and regimen
(single and repeat dose) after accounting for the diurnal variation in placebo response.
The key model parameters to be estimated are: time for onset of effect, overall apparent
potency, Emax, elimination half life of drug in lung biophase, and parameters describing
the diurnal variations of pulmonary function (FEV1).
11.2.1.
There were a total of 588 subjects in the ITT population each contributing 1 trough FEV1
value on Day 28 for the dose response analysis. The model parameters E0 (placebo
effect), ED50 and Emax were estimated with good precision but inter-subject variability
could only be estimated for the placebo response. No estimation of inter-subject
variability on potency (ED50) or maximum effect (Emax) was possible; this is not
unexpected given the current parallel-dose study design with 1 datum per subject.
The covariates, namely, age, baseline FEV1 and gender showed statistically significant
effect and thus explain the inter-subject variability in the placebo response (intercept E0).
Based on statistical criteria for model selection, the parameters of the dose response for
the optimal model and the associated precision of the estimates is given below
(Table 39). This is also supported by the typical range of diagnostics as shown in
Attachment 4. The model simulated LS Mean profile has been overlaid with observed
LS Mean Difference from placebo in Figure 21.
Table 39
Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error
Value
% RSE
0.243
20
16.1
11
0.733
18
-0.392
12
2.65
21
-0.166
24
Proportional: CV 12%
Additive: Standard Deviation 0.16
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5th CI
0.149
12.5
0.480
-0.482
1.57
-0.245
95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087
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Figure 21
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]
10
20
30
40
50
OD Dose (ug)
11.2.2.
The dataset for modelling time course of FEV1 comprised 548 subjects giving a total of
14333 individual FEV1 values over time post dose for both Day 1 and Day 28 over the
dose range 0 g (placebo) to 50 g od. Separate analyses were performed for both Day
1, Day 28 and combined Day 1 and Day 28. There was no marked difference in model
parameters between the separate Day 1 and Day 28 analyses. The various models
explored with final model parameters are provided in Attachment 5 and the salient results
from the final model are summarised below.
One application of the population K-PD model was to simulate the time course of FEV1
after placebo and each treatment after adjusting for the diurnal variations in pulmonary
function. Figure 22 shows the reasonable predictions of the K-PD model for placebo and
one of the doses at 25 g. Additional results provided in Attachment 4.
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Figure 22
0.40
LSMean Obs
Mean model
Day 28 Placebo
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
0
10
12
14
16
18
20
22
24
26
Time (h)
0.40
Day 28 25ug
0.35
0.30
0.25
LSMean Obs
Mean model
0.20
0.15
0.10
0.05
0.00
-0.05
0
10
12
14
16
18
20
22
24
26
Time (h)
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pg/mL (upper 95%CI) would be associated with a maximum pulse rate change of 10
bpm. In the present study, very limited plasma data showed measurable drug levels
(LLQ=30 pg/mL) at doses 6.25 g. Whilst the majority of subjects had evaluable peak
drug levels at 12.5 g (often based on n=1 data point), even at the highest dose of 50 g
the geometric mean peak drug levels were only 223 pg/mL (upper 95%CI for peak drug
levels was 262pg/mL). There were no clear relationships between peak drug levels and
change in pulse rate due to the limited and narrow range of measurable drug levels of
GW642444 in asthmatics.
Figure 23 maps the therapeutic index of GW642444 in asthmatics over the dose range up
50 g OD. It clearly shows the good margin of safety (maximum HR increase) versus
effective dose response (observed LSMean and overlay with model fitted curve). Even at
the highest dose of 50 g at steady state there is only a marginal increase of 2.7 bpm.
Therapeutic Index mapping dose-response for efficacy and safety
Day 28
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3
0.30
0.25
Threshold
0.20
0.15
0.10
0.05
0.00
-0.05
0
10
20
30
OD Dose (ug)
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40
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11.3.
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Pharmacokinetic/Pharmacodynamic Summary
GW642444M shows a good therapeutic margin over the dose range studied. There
were limited measurable drug levels above the quantification limit of 30 pg/mL in
doses < 25 g. There was no clear relationship between systemic exposure
(observed Cmax over period 2-30 min post-dose) and any systemic PD endpoint
(pulse rate, QTc, glucose or potassium).
Using a population dose response model, the potency (ED50) of GW642444M was
16.1 g [95%CI: 12.5-19.7 g]. The predicted maximum FEV1 (Emax- after
adjusting for placebo) was 243 mL [95%CI:149-337 mL].
The lower doses of 12.5 and 6.25 g also showed sustained and prolonged duration
of effect, albeit lower than that observed at and above 25 g. This consistency in
prolonged efficacy at all doses and the estimated peak to trough ratio close to unity
across all doses highlight the intrinsic prolonged bronchodilator activity of
GW642444 in asthma.
12.
12.1.
Discussion
The aim of this Phase IIb study was to investigate the dose response, efficacy and safety
of GW642444M, administered OD in the evening to asthmatics, to generate data to
inform on the selection of dose of GW642444M to be carried forward into the Phase III
studies where GW642444M will be combined with the inhaled corticosteroid
GW685698X to form a once daily LABA/ICS combination product.
This placebo controlled study investigated five doses of GW642444M (3 g, 6.25 g,
12.5 g, 25 g and 50 g). The 3 g dose was included as a potential no-effect dose.
The 50 g dose was included as a likely supra-therapeutic dose to help establish the
therapeutic index for GW642444M and to assess whether or not a plateau had been
achieved. The population recruited were symptomatic subjects with persistent asthma
who had a percentage predicted FEV1 at baseline of between 40% and 90% and
reversibility as demonstrated by an increase in FEV1 of 12% and 200 mL following 400
g albuterol/salbutamol. Subjects were required to be symptomatic despite treatment
with background ICS, representing a population who are suitable for a step-up in therapy
according to national [NIH, 2007] and international [GINA, 2006] treatment guidelines.
Subjects were stratified at randomisation according to baseline percentage predicted
FEV1 (40 to 65% and >65 to 90%) to investigate if the dose response to GW642444M
was similar in subjects with different disease severities.
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The primary endpoint of mean change from baseline at Day 28 in trough (evening prebronchodilator and pre-dose) FEV1 was selected as a measure of 24-h bronchodilation
with FEV1 as an accepted reproducible measure of lung function.
Within the ITT Population, the baseline demographics across the six treatment groups
were similar with the mean age of the study population ranging from 39.9 years to 44.4
years (27 subjects [4%] were 12-17 years of age), and the majority of the subjects having
had asthma for longer than 10 years (64% to 74%). The baseline mean percent of
predicted normal FEV1 across groups ranged from 65.3% to 67.6% and subjects
demonstrated a high degree of reversibility (mean percent reversibility 24.2 % to 27.4 %
across the groups). All subjects were receiving ICS at baseline from 100 to 2000 g
daily of BDP or equivalent with the mean ICS dose across each of the treatment groups
ranging from 698 g to 814 g daily. As such, the subjects in the study represented a
population of moderately severe persistent asthmatics who were uncontrolled despite ICS
therapy.
Results from the primary efficacy endpoint demonstrate that OD treatment with
GW642444M provides bronchodilation out to 24-h supporting OD dosing. Dosedependent improvements in trough FEV1 following 28-days of treatment were
statistically significant compared to placebo at the 12.5 g (p=0.011), 25 g (p=0.016)
and 50 g (p=0.001) doses (mean treatment differences of 130 mL, 121 mL and 162 mL,
respectively). A statistically significant linear trend in dose response in trough FEV1
(p=0.003) demonstrated the overall efficacy of GW642444M, despite a placebo effect of
147 mL versus baseline. The results from the per protocol analysis and the repeated
measures analysis of the primary endpoint also confirmed a statistically significant
superiority for the 12.5 g, 25 g and 50 g doses relative to placebo (all p<0.05).
Although none of the doses produced an increase in the adjusted mean trough FEV1 of
200 mL this appeared to be related to the pronounced placebo response observed in the
study. The unadjusted mean changes from baseline were all well in excess of 200 mL for
the 12.5 g, 25 g and 50 g groups (278 mL, 269 mL and 309 mL, respectively). The
reason for the pronounced placebo effect is not entirely clear, though it may have been
related to timing of the trough measurement which was recorded in the evening at a time
when lung function tends to be higher as a result of the natural circadian rhythm in
airway tone. Alternatively it may have been difficult to show such a magnitude of effect
in a population who were already receiving, in some instances, high doses of ICS, and
who may have increased their compliance with ICS as a result of being in the study.
The analysis by percent predicted FEV1 stratum suggests a broadly similar dose response
between the lower stratum (40% - 65%) and upper stratum (>65% - 90%) with CIs
substantially overlapping for all doses except for the 3 g dose. This suggests that the
dose response relationship was similar in subjects with more severe airway obstruction
compared to those with milder obstruction.
Serial FEV1 measurements taken on both Days 1 and 28 showed statistically significant
increases versus placebo in weighted mean change from baseline FEV1 (0-24 h) for all
doses of GW642444M except the 6.25 g dose on Day 1. However, the greatest
improvements were seen in the 12.5 g, 25 g and 50 g GW642444M groups (0.130 L
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to 215 mL on Day 1, and 0.142 mL to 172 mL on Day 28) though separation between all
the doses was more evident on Day 1 than on Day 28.
The serial FEV1 profiles also provide evidence of the 24-h duration of GW642444M. An
analysis of the peak value in FEV1 taken over the first 4 h compared to the trough FEV1
value taken over hours 23-24 revealed that the ratio of peak to trough across all the five
doses studied was close to 1. The ratio did not differ greatly as the dose increased,
remaining at or below 1.06 for all doses, suggesting that the 24-h duration of action was
an intrinsic property of the molecule rather than a function of increasing dose.
Other analyses also provided evidence of a dose-response across the doses studied and
confirmed the 24-h bronchodilation achievable with once-daily dosing with
GW642444M. Repeated measures analysis of the primary endpoint demonstrated a dosedependent response with 24-h statistically significant improvements in trough FEV1
compared with placebo for 12.5 g and 25 g GW642444M at 23 and 24 h post-dose on
Day 28; as well as 50 g GW642444M pre-dose on Day 7, Day 14 and Day 28, and at
23-24 h post-dose on Day 28.
Evening PEF, measured before the administration of study medication and therefore 24-h
after the preceding dose, increased with ascending GW642444M dose. All doses
produced a statistically significant improvement in evening PEF min relative to placebo
with the 25 g and 50 g doses producing improvements in PEF in excess of >30 L/min
(AM and PM PEF all p<0.001 except for the 3 g dose). A sharp fall was seen in
evening PEF for all treatments, including placebo, from Day1 to Day 2. The reason for
this may relate to the timing of the measurements which on Day 1 were performed in the
clinic in the late afternoon as opposed to the recordings made on subsequent days which
were performed immediately prior to the subjects taking their study medication in the
evening. Thus the fall observed between Day 1 and Day 2 may therefore be due to the
circadian variation in airway tone which tends to result in the highest values for lung
function values being seen in the late afternoon before falling back later in the day. No
such fall between Day 1 and Day 2 was observed in morning PEF which was recorded at
a similar time of day throughout the study. Morning PEF also increased in a dosedependent fashion with the 12.5 g and 25 g doses producing improvements relative to
placebo in excess of 30 L/min and the 50 g dose increasing morning PEF above 40
L/min.
Symptom-free and rescue-free 24-h periods demonstrated a dose-dependent increase up
to 25 g. No additional improvements were seen at the 50 g dose. This pattern was
repeated when symptom-free nights and days and rescue-free nights and days were
looked at separately.
The weighted mean FEV1 over the first 4 h on Day 1 and Day 28 increased with
ascending dose. All doses were statistically significant compared to placebo (all
p0.037) but only the 25 g and 50 g doses achieved a >200 mL improvement both on
Day 1 and Day 28 (p<0.001). The maximum increase in FEV1 over the first 4 h also
improved in a dose-related fashion with greatest improvement seen with the 50 g dose.
Analysis of the proportion of subjects with a combined increase of 200 mL and 12%
over baseline FEV1 in the 4 h following the dose at the clinic, demonstrated that a
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consistently higher percentage of subjects achieved the threshold with the 25 g and 50
g GW642444M doses (50% of subjects at most timepoints) on Day 1 and Day 28
compared with the 3 g, 6.25 g and 12.5 g doses, although the proportion of subjects
between the 25 g and 50 g doses were very similar. Analysis of the proportion of
subjects with a combined increase of 200 mL and 12% over baseline FEV1 over 24 h
post-dosing showed that the majority of subjects (>50% at most timepoints) receiving the
25 g and 50 g doses consistently maintained the improvement in lung function over
this time interval.
Withdrawals due to efficacy were highest in the placebo (9%) and 3 g (12%) treatment
groups and 5% in the other treatment groups. No subjects were withdrawn due to lack
of efficacy in the 50 g GW642444M group suggesting that, with the exception of the 3
g dose all doses were efficacious though the efficacy tended to increase with increasing
dose.
The response to albuterol/salbutamol following treatment with GW642444M was
investigated comparing the response at Screening and Day 1 with Day 28. There was no
difference between any of the doses and placebo with regards to the response to
albuterol/salbutamol at any of the time points investigated suggesting that there was no
evidence of tolerance developing to the bronchodilator response from short-acting 2agonists with GW642444M.
The safety of GW642444M was assessed by the occurrence of AEs and routine
laboratory assessments including measures which are known to be affected by -2agonists including serum potassium and glucose levels. Potential signs of any cardiac
effects were assessed using 12-lead ECG measurements.
The incidence of AEs was similar across all the GW642444M treatment groups and
comparable to placebo and there was no dose-related increase in the frequency of the
most commonly reported AEs. Drug-related AEs were reported at a very low incidence
with no more than 8 subjects on any treatment reporting an individual event.
Pharmacologically predictable AEs such as palpitations and tremor were also infrequent
and were similar in frequency to placebo with <1% of subjects reporting tremor, seen in
the 6.25 g dose group only. A total of 4 subjects were withdrawn due to subject
reaching protocol-defined stopping criteria, with the events of ventricular tachycardia
(placebo), AV block second degree (12.5 g GW642444M), T-wave amplitude decreased
(6.25 g GW642444M), and PR prolongation (6.25 g GW642444M). These subjects
experienced related AEs as a sub reason for withdrawal. Two subjects withdrew due to
the AEs of Psychomotor hyperactivity wired, feeling jittery and insomnia (3 g
GW642444M), and Increase in allergy symptoms and Pyrexia (25 g GW642444M). No
SAEs were reported. Overall, the AE data are very reassuring in that the frequency was
similar to placebo with no evidence of the frequency increasing as the dose increased and
no unexpected AEs. Asthma exacerbations were infrequent, with the highest percentage
of events in the placebo and 3 g GW642444M groups (4% and 7%, respectively),
compared with 0% to 3% in the other groups.
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No clinically relevant changes were noted in any of the haemotology, clinical chemistry
and urinalysis assessments. Small differences in incidence of values outside normal
range for CPK were observed when comparing active treatment arms and placebo,
although there was no dose response and most of the values were within twice the upper
limit of normal. No safety concerns were observed with liver function tests and no
treatment related changes were apparent in the vital signs. Small increases in pulse rate
were observed with the 50 g dose but as these changes were within the predefined
clinically relevant threshold (6 bpm) no safety concerns were raised for pulse rate. For
potassium and glucose, maximum and weighted mean changes from baseline (0-4 h),
including changes versus placebo, did not exceed the predefined levels of clinically
relevant concern (-0.3 mmol/L and 1.5 mmol/L for potassium and glucose, respectively).
No AEs of hypokalaemia were reported.
Although for the 50 g dose a statistically significant difference in mean post-dose serial
QTc(F) (0-4 h) change from baseline versus placebo was recorded of 5.0 msec on Day 7 at
10 minutes post-dose, it is recognised that mean QT prolongation changes of 5-20 msec
would represent a grey zone with an unclear risk of arrhythmia, whilst agents causing
mean QT prolongation of >20 msec would substantially increase the risk of proarrhythmia [FDA Guidance for Industry, 2005]. Furthermore, the use of the stated
thresholds is most relevant for the conduct of a Thorough QT study [FDA Guidance for
Industry, 2005].
For QTc(B) some treatment differences were observed with the 50 g dose which were
above the 5 msec threshold of clinical concern for this study, although as stated above,
the clinical significance of this observation is unclear. Treatment differences 5 msec
(and 12.5 msec) were observed between 10 min and 1 h following dosing on all the
study visit days. Treatment differences of 5 msec (and 8.2 msec) were also observed
for the 25 g dose on Day 1 at 10 min and on Day 14 at 10 min and 1 h post-dose.
However, the QTc(B) has been suggested to overestimate the QTc when heart rate
increases [Milic M, 2008] which occurs with 2-agonists as the dose is increased.
Importantly no increase in QTc was seen when the more appropriate Fridericias
correction was used. The use of the more accurate measure QTc(F) is supported by
analysis of QTc(F) and QTc(B) heart rate relationship, which increased for QTc(B) whilst
remained unchanged for QTc(F).
Overall, GW642444M was well tolerated across all the doses in this study.
The results from this study support the 24-h duration of bronchodilation with OD evening
dosing GW64244M. A dose-response was seen which was consistent with the rationale
that the 3 g represented a no-effect dose and the results of the 25 g and 50 g were
very similar suggesting that 50 g may represent a plateauing of the dose response curve
with regards to some of efficacy endpoints. Although the 12.5 g dose and 25 g doses
were similar for trough FEV1 on Day 28, across a number of other efficacy endpoints
there was a small incremental benefit of the 25g over the 12.5g dose. The 25g and
12.5g doses separated on the proportion of subjects who achieved a 200 mL and 12%
improvement over baseline over 24 h with the majority of subjects at most time points
achieving this threshold with the 25 g dose, compared with 45% with the 12.5 g dose.
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Additionally, greater improvements in symptom-free and rescue- free 24-h periods and
morning and evening peak flow were observed with 25 g versus 12.5 g dose.
Maximum increase and peak FEV1 was also higher with 25 g than with 12.5 g.
In conclusion, the data from this study suggests that the minimally effective optimal
doses for GW642444M to be carried forward into Phase III would be either the 12.5g or
25 g dose representing doses with high efficacy and good tolerability.
Pharmacokinetics / Pharmacodynamics
Pharmacokinetics and Systemic Pharmacokinetics / Pharmacodynamics
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95%CI obtained at the highest dose of 50 g OD in the present study [LSMean 162 mL.
95%CI: 62-261 mL]. Based on a model for time course of FEV1 after accounting for
diurnal variation, GW642444M has long pulmonary residency with an estimated
elimination half life of the drug in the lung biophase (T=26h [95%CI 23-29h) based on
the dose-time-response analysis.
This sustained lung drug residency would also explain the observed peak to trough ratio
close to unity at all treatment doses. Thus the combination of high pulmonary potency of
GW642444M, sustained residency of the drug and peak to trough ratio close to unity
would support the rationale for once daily potential dosing regimen in asthmatics.
12.2.
Conclusions
The Per Protocol and repeated measures analyses confirmed the results from the
primary analysis by demonstrating the superiority of 12.5 g, 25 g and 50 g doses
GW642444M relative to placebo.
Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, treatment with 25
g and 50 g GW642444M resulted in consistently greater improvements in lung
function (weighted mean 24-h serial FEV1, proportion of subjects achieving 200
mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h maximum and
peak FEV1), morning and evening PEF as well as symptoms and rescue use
(percentage of symptom- and rescue free 24-h periods).
A greater withdrawal rate due to lack of efficacy with the lower doses compared to
the higher GW642444M doses are consistent with the findings of the primary and
other efficacy analyses.
Broadly similar dose response effects were found for the lower and upper strata,
suggesting that different doses of GW642444M may not be required for different
severities of asthma.
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There were no clinically relevant increases from baseline versus placebo in serial,
weighted mean or maximum QTc(F) (0-4 h) for any treatment group, at any time
point. Although increases in mean serial QTc(B) from baseline versus placebo of 6
msec to 12.5 msec in the 25 g and 50 g GW642444M groups were above the 5
msec threshold of clinical concern, QTc(F) was acknowledged as the more robust
correction for drugs that are associated with increased heart rate, with QTc(B) being a
poorer correction factor.
Potassium and glucose values did not exceed the predefined levels of clinically
relevant concern. No AEs of hypokalaemia were reported.
PK analysis showed that GW642444 shows a good therapeutic margin over the dose
range studied. There were limited measurable drug levels above the quantification
limit of 30 pg/mL up to 25 g dose, without a clear relationship between systemic
exposure (observed Cmax over period 2-30 min post-dose) and any systemic PD
endpoint (pulse rate, QTc, glucose or potassium).
In conclusion, the data from this study suggest that the minimally effective doses for
GW642444M to be carried forward into Phase III would be either the 12.5 g or 25
g dose representing doses with high efficacy and good tolerability.
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REFERENCES
Beasley R. The Global Burden of Asthma Report, Global Initiative for Asthma (GINA).
Available from http://www.ginasthma.org 2004.
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for
Non-Antiarrhythmic Drugs. FDA Guidance for Industry. October 2005. ICH. E14,
(2005).
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and
Prevention 2006. Global Initiative for Asthma, www.ginasthma.org; 2006.
GlaxoSmithKline Document number: WD2006/02197/00. The Validation of a Method
for the Determination of GW642444 (range 30 to 15000 pg/mL), GW630200 (range 90 to
45000 pg/mL) and GSK932009 (range 180 to 90000 pg/mL) in Human Plasma using
HPLC-MS/MS. Validation Report, 5-Sept-2006.
GlaxoSmithKline Document number: WD2006/02527/00. Validation of a Method for
the Determination of GI179710 in Human Plasma (range 1 to 1000 ng/mL) using HPLC
MS/MS. Validation Report, 8-Nov-2006.
IND 74,696, 08 November 2007, SN0000, Vol. 60.
NIH. Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NHLBI,
August; 2007. NIH publication no. 08-4051.
Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive
summary of the GINA Dissemination Committee report. Allergy 2004;59(5):469-78.
Milic M, Bao X, Rizos, D, et al. Literature Review and Pilot Studies of the Effect of QT
Correction Formulas on Reported 132-Agonist-Induced QTc Prolongation. Clinical
Therapeutics 2006;28(4):582-90.
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This section contained patient narratives which are textual descriptions of medical history,
treatment and outcome for individual patients who experienced a clinically important adverse
event including serious adverse events during the trial. They have been excluded to protect
patient privacy. This data may be made available subject to an approved research proposal and
a determination of the ability to provide information from the specific narratives whilst protecting
the patients privacy. For further information please see the Patient Level Data section of
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134
136
137
138
139
140
141
142
154
155
157
158
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160
161
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187
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135
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228
Page 1 of 1
Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.1
Subject Withdrawals Over Time
100
90
70
60
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136
80
50
40
30
20
10
1 Week
2 Weeks
3 Weeks
4 Weeks
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Kaplan-Meier Estimate of time to withdrawal. Subjects are represented from their date of randomisation to their date
of study drug discontinuation
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0
Randomisation
Page 1 of 1
Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.2
Subject Withdrawals due to Lack of Efficacy Over Time
30
20
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25
15
10
1 Week
2 Weeks
3 Weeks
4 Weeks
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy
YM2008/00019/00
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0
Randomisation
Protocol: B2C109575
Population: Total
Page 1 of 1
Table 6.1
Summary of Subject Populations
Population
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
--------------------------------------------------------------------------------------------------------Total
1140
Randomised
103
102
102
102
103
102
614
Intent-to-Treat (ITT) 102 (>99%) 101 (>99%) 101 (>99%) 100 (98%) 101 (98%) 102 (100%) 607 (99%)
Per Protocol (PP)
98 (95%)
97 (95%)
98 (96%)
98 (96%)
93 (90%)
99 (97%) 583 (95%)
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Note: 92 subjects in the Total population were previously screened but are only counted once.
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Total: All subjects screened and for whom a record exists on the study database.
ITT: All randomised subjects who received at least a single dose of trial medication.
PP: All subjects in the ITT population who do not have any full protocol deviations.
Protocol: B2C109575
Population: Total
Page 1 of 1
Table 6.2
Summary of Reasons For Withdrawal Prior to Randomisation
Total
(N=1140)
---------------------------------------------------Withdrawals prior to randomisation
525 (46%)
1
3
29
0
16
19
457
(<1%)
(<1%)
(3%)
(1%)
(2%)
(40%)
139
This subject is not included in
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this summary.
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Page 1 of 1
Table 6.3
Summary of End of Study Record
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Completion Status
Completed
86 (84%)
84 (83%)
91 (90%)
88 (88%)
93 (92%)
97 (95%)
539 (89%)
Prematurely Withdrawn
16 (16%)
17 (17%)
10 (10%)
12 (12%)
8 (8%)
5 (5%)
68 (11%)
0
9
2
4
0
(9%)
(2%)
(4%)
1 (<1%)
12 (12%)
3 (3%)
7 (7%)
0
0
5
2
3
0
2
0
0
0
0
0
0
0
1
0
1
0
3
0
2
0
2
0
0
3
0
1 (<1%)
0
7
1 (<1%)
0
0
0
1 (<1%)
0
5
2
0
0
0
0
3
0
0
0
0
3
(3%)
(3%)
(2%)
(2%)
(2%)
(7%)
(5%)
(2%)
0
3
3
0
0
1
1
1
(5%)
(2%)
(3%)
(1%)
(1%)
(3%)
(3%)
(1%)
(1%)
(1%)
1 (<1%)
4 (4%)
3 (3%)
2 (2%)
0
0
0
0
0
0
2 (<1%)
33 (5%)
12 (2%)
17 (3%)
0
2
0
0
0
0
0
0
0
0
0
0
0
10 (2%)
0
4 (<1%)
0
4 (<1%)
0
0
2
(2%)
(2%)
2 (2%)
0
0
0
0
1 (<1%)
Note: Only 1 primary reason can be chosen, but there can be multiple sub reasons.
0
2
(2%)
0
18
2 (2%)
0
0
0
2 (2%)
1 (<1%)
16
2
0
1
4
6
(3%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
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3 (3%)
0
1 (<1%)
0
1 (<1%)
0
(3%)
(3%)
0
3 (3%)
2 (2%)
1 (<1%)
0
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Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.4
Summary of Attendance at Each Clinic Visit
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Visit
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Screening
102 (100%)
101 (100%)
101 (100%)
100 (100%)
101 (100%)
102 (100%)
607 (100%)
Day 1
102 (100%)
101 (100%)
101 (100%)
100 (100%)
101 (100%)
102 (100%)
607 (100%)
Day 7
95 (93%)
98 (97%)
99 (98%)
97 (97%)
100 (>99%)
100 (98%)
589 (97%)
Day 14
93 (91%)
92 (91%)
96 (95%)
92 (92%)
95 (94%)
98 (96%)
566 (93%)
Day 28
89 (87%)
87 (86%)
91 (90%)
90 (90%)
94 (93%)
98 (96%)
549 (90%)
Follow Up
99 (97%)
97 (96%)
99 (98%)
96 (96%)
99 (98%)
100 (98%)
590 (97%)
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Page 1 of 12
Table 6.5
Summary of Number of Subjects by Centre
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------3 (3%)
4 (4%)
4 (4%)
7 (7%)
6 (6%)
12 (12%)
36 (6%)
1 (<1%)
3 (3%)
0
4 (4%)
2 (2%)
5 (5%)
15 (2%)
0
0
1 (<1%)
2 (2%)
0
2 (2%)
5 (<1%)
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
3 (<1%)
1 (<1%)
1 (<1%)
3 (3%)
0
1 (<1%)
3 (3%)
9 (1%)
0
0
0
0
3 (3%)
1 (<1%)
4 (<1%)
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Population: Intent-to-Treat
Page 2 of 12
Table 6.5
Summary of Number of Subjects by Centre
France
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------2 (2%)
0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
7 (1%)
2 (2%)
0
1 (<1%)
1 (1%)
1 (<1%)
1 (<1%)
6 (<1%)
0
0
0
1 (1%)
0
0
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
4
0
4
(4%)
(4%)
4 (4%)
1 (<1%)
3 (3%)
1 (<1%)
0
1 (<1%)
14 (2%)
4 (<1%)
10 (2%)
143
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3 (3%)
2 (2%)
1 (<1%)
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Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 12
Table 6.5
Summary of Number of Subjects by Centre
144
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Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------4 (4%)
6 (6%)
3 (3%)
6 (6%)
4 (4%)
2 (2%)
25 (4%)
1 (<1%)
0
0
1 (1%)
1 (<1%)
0
3 (<1%)
0
0
0
1 (1%)
0
0
1 (<1%)
2 (2%)
4 (4%)
2 (2%)
2 (2%)
2 (2%)
0
12 (2%)
0
0
0
1 (1%)
0
0
1 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
2 (<1%)
0
0
1 (<1%)
0
0
1 (<1%)
2 (<1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
0
2 (2%)
0
1 (1%)
0
0
3 (<1%)
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Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 12
Table 6.5
Summary of Number of Subjects by Centre
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------2 (2%)
1 (<1%)
0
0
3 (3%)
1 (<1%)
7 (1%)
2 (2%)
1 (<1%)
0
0
3 (3%)
1 (<1%)
7 (1%)
3
0
0
3
(3%)
(3%)
4 (4%)
0
1 (<1%)
3 (3%)
4
0
2
2
(4%)
(2%)
(2%)
3 (3%)
1 (<1%)
1 (<1%)
1 (<1%)
3 (3%)
0
2 (2%)
1 (<1%)
21 (3%)
1 (<1%)
7 (1%)
13 (2%)
145
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4 (4%)
0
1 (<1%)
3 (3%)
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Population: Intent-to-Treat
Page 5 of 12
Table 6.5
Summary of Number of Subjects by Centre
146
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Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------7 (7%)
13 (13%)
11 (11%)
12 (12%)
8 (8%)
12 (12%)
63 (10%)
1 (<1%)
1 (<1%)
3 (3%)
1 (1%)
0
2 (2%)
8 (1%)
1 (<1%)
2 (2%)
3 (3%)
4 (4%)
1 (<1%)
4 (4%)
15 (2%)
2 (2%)
2 (2%)
2 (2%)
4 (4%)
3 (3%)
3 (3%)
16 (3%)
2 (2%)
4 (4%)
0
3 (3%)
2 (2%)
1 (<1%)
12 (2%)
1 (<1%)
0
1 (<1%)
0
0
0
2 (<1%)
0
2 (2%)
0
0
0
0
2 (<1%)
0
2 (2%)
2 (2%)
0
2 (2%)
2 (2%)
8 (1%)
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Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 12
Table 6.5
Summary of Number of Subjects by Centre
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Page 7 of 12
Table 6.5
Summary of Number of Subjects by Centre
South Africa
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------4 (4%)
4 (4%)
5 (5%)
2 (2%)
1 (<1%)
3 (3%)
19 (3%)
1 (<1%)
2 (2%)
2 (2%)
1 (1%)
0
1 (<1%)
7 (1%)
0
2 (2%)
0
1 (1%)
0
0
3 (<1%)
3 (3%)
0
3 (3%)
0
1 (<1%)
2 (2%)
9 (1%)
2
0
2
0
(2%)
(2%)
2
0
2
0
(2%)
(2%)
1
0
1
0
(1%)
(1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
1 (<1%)
0
0
10 (2%)
1 (<1%)
7 (1%)
2 (<1%)
148
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3 (3%)
0
2 (2%)
1 (<1%)
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Population: Intent-to-Treat
Page 8 of 12
Table 6.5
Summary of Number of Subjects by Centre
Thailand
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------1 (<1%)
3 (3%)
0
2 (2%)
2 (2%)
0
8 (1%)
1 (<1%)
2 (2%)
0
2 (2%)
1 (<1%)
0
6 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
2 (<1%)
(2%)
(2%)
2 (2%)
1 (<1%)
1 (<1%)
5 (5%)
4 (4%)
1 (<1%)
1
1
0
(1%)
(1%)
3 (3%)
2 (2%)
1 (<1%)
5 (5%)
4 (4%)
1 (<1%)
18 (3%)
14 (2%)
4 (<1%)
149
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2
0
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Population: Intent-to-Treat
Page 9 of 12
Table 6.5
Summary of Number of Subjects by Centre
0
8
8
(8%)
(8%)
1
6
2
(1%)
(6%)
(2%)
0
5
7
(5%)
(7%)
0
4
2
(4%)
(2%)
2 (<1%)
33 (5%)
32 (5%)
150
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0
4 (4%)
10 (10%)
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Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 12
Table 6.5
Summary of Number of Subjects by Centre
151
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Country
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Investigator
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------Russian
10 (10%)
3 (3%)
6 (6%)
6 (6%)
8 (8%)
8 (8%)
41 (7%)
Federation
1 (<1%)
2 (2%)
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
8 (1%)
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
3 (<1%)
3 (3%)
0
0
1 (1%)
0
2 (2%)
6 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
1 (1%)
2 (2%)
1 (<1%)
4 (<1%)
6 (6%)
0
1 (<1%)
3 (3%)
4 (4%)
2 (2%)
16 (3%)
0
0
2 (2%)
0
0
1 (<1%)
3 (<1%)
YM2008/00019/00
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Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 12
Table 6.5
Summary of Number of Subjects by Centre
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Population: Intent-to-Treat
Page 12 of 12
Table 6.5
Summary of Number of Subjects by Centre
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Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------36 (35%)
34 (34%)
35 (35%)
39 (39%)
37 (37%)
38 (37%)
219 (36%)
0
2 (2%)
1 (<1%)
1 (1%)
1 (<1%)
1 (<1%)
6 (<1%)
1 (<1%)
0
3 (3%)
1 (1%)
0
3 (3%)
8 (1%)
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
1 (1%)
1 (<1%)
1 (<1%)
3 (<1%)
0
0
1 (<1%)
1 (1%)
0
0
2 (<1%)
1 (<1%)
0
0
1 (1%)
1 (<1%)
0
3 (<1%)
0
1 (<1%)
1 (<1%)
0
0
0
2 (<1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
0
3 (<1%)
0
2 (2%)
0
0
1 (<1%)
2 (2%)
5 (<1%)
1 (<1%)
4 (4%)
2 (2%)
1 (1%)
0
2 (2%)
10 (2%)
1 (<1%)
1 (<1%)
3 (3%)
1 (1%)
2 (2%)
0
8 (1%)
3 (3%)
1 (<1%)
1 (<1%)
3 (3%)
0
1 (<1%)
9 (1%)
1 (<1%)
2 (2%)
2 (2%)
0
1 (<1%)
1 (<1%)
7 (1%)
1 (<1%)
0
1 (<1%)
0
0
0
2 (<1%)
0
0
1 (<1%)
1 (1%)
0
0
2 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
2 (<1%)
2 (2%)
2 (2%)
2 (2%)
3 (3%)
4 (4%)
4 (4%)
17 (3%)
2 (2%)
3 (3%)
0
1 (1%)
4 (4%)
3 (3%)
13 (2%)
3 (3%)
1 (<1%)
2 (2%)
3 (3%)
4 (4%)
1 (<1%)
14 (2%)
0
4 (4%)
5 (5%)
4 (4%)
2 (2%)
2 (2%)
17 (3%)
1 (<1%)
0
0
0
1 (<1%)
2 (2%)
4 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
7 (1%)
2 (2%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
6 (<1%)
2 (2%)
3 (3%)
2 (2%)
7 (7%)
4 (4%)
4 (4%)
22 (4%)
2 (2%)
2 (2%)
1 (<1%)
0
3 (3%)
1 (<1%)
9 (1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
1 (<1%)
0
7 (1%)
2 (2%)
3 (3%)
2 (2%)
1 (1%)
1 (<1%)
7 (7%)
16 (3%)
4 (4%)
1 (<1%)
1 (<1%)
3 (3%)
3 (3%)
0
12 (2%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.6
Summary of Inclusion/Exclusion Criteria Deviations
Placebo 3mcg
6.25mcg 12.5mcg 25mcg
50mcg
Total
(N=102) (N=101) (N=101) (N=100) (N=101) (N=102) (N=607)
--------------------------------------------------------------------------------------------------------Any criteria deviations
0
1 (<1%) 2 (2%) 0
2 (2%) 0
5 (<1%)
Exclusion to Run-In:
Systemic corticosteroids or anti-IgE
medications within 12 weeks of Visit 1
Asthma exacerbation requiring OCS within
3 months of Visit 1
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
3 (<1%)
(2%)
154
CONFIDENTIAL
Randomisation Criteria:
No 12-lead ECG abnormalities
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 6.7
Summary of Protocol Deviations
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Full Deviations
4 (4%)
4 (4%)
3 (3%)
2 (2%)
8 (8%)
3 (3%)
24 (4%)
1 (<1%)
0
0
1 (<1%)
0
0
2 (2%)
1 (<1%)
(3%)
(2%)
(2%)
1 (<1%)
(1%)
0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
0
2 (2%)
0
0
1 (<1%)
0
0
0
0
0
2
1 (<1%)
0
0
1 (<1%)
0
3 (3%)
0
0
1 (<1%)
0
0
2 (2%)
1
1
6
2
1
12
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
155
(3%)
4 (<1%)
YM2008/00019/00
B2C109575
(2%)
CONFIDENTIAL
Failure of inclusion/exclusion/
randomisation criteria
Exclusion Criteria 3
Exclusion Criteria 11
Inclusion Criteria 4
Randomisation 1
Randomisation 2
Received protocol prohibited
medications during the study
Treatment compliance < 80%
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 6.7
Summary of Protocol Deviations
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Partial Deviations
4 (4%)
8 (8%)
4 (4%)
4 (4%)
1 (<1%)
1 (<1%)
22 (4%)
2
(2%)
(3%)
(2%)
(1%)
1 (<1%)
(1%)
1 (<1%)
(3%)
(2%)
(2%)
(1%)
1 (<1%)
1 (<1%)
2 (<1%)
4 (<1%)
1 (<1%)
1 (<1%)
(3%)
YM2008/00019/00
B2C109575
(1%)
CONFIDENTIAL
156
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.8
Summary of Demographic Characteristics
Intent-to-Treat
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Age (y)
n
102
101
101
100
101
102
607
Mean
39.9
44.4
42.4
41.3
42.2
44.0
42.4
SD
15.60
13.50
14.13
15.33
14.27
15.22
14.72
Median
42.0
45.0
44.0
43.5
45.0
45.5
44.0
Min.
12
15
16
12
12
13
12
Max.
68
74
80
72
70
73
80
7 (7%)
89 (87%)
6 (6%)
2 (2%)
92 (91%)
7 (7%)
2 (2%)
94 (93%)
5 (5%)
7 (7%)
86 (86%)
7 (7%)
5 (5%)
93 (92%)
3 (3%)
4 (4%)
90 (88%)
8 (8%)
27 (4%)
544 (90%)
36 (6%)
157
Sex
n
Female
Male
102
61 (60%)
41 (40%)
101
52 (51%)
49 (49%)
101
51 (50%)
50 (50%)
100
56 (56%)
44 (44%)
101
61 (60%)
40 (40%)
102
57 (56%)
45 (44%)
607
338 (56%)
269 (44%)
Ethnicity
n
102
Hispanic/Latino
9 (9%)
Not Hispanic/Latino 93 (91%)
101
13 (13%)
88 (87%)
101
10 (10%)
91 (90%)
100
13 (13%)
87 (87%)
101
12 (12%)
89 (88%)
102
22 (22%)
80 (78%)
607
79 (13%)
528 (87%)
102
165.3
10.94
165.0
108
188
101
169.5
11.30
170.0
135
200
101
167.3
9.67
167.0
149
193
100
168.5
10.06
170.0
140
191
101
167.1
9.70
167.0
150
193
102
167.8
9.97
168.0
147
198
607
167.6
10.33
168.0
108
200
Weight (kg) n
Mean
SD
Median
Min.
Max.
101
77.16
18.644
72.00
48.0
127.0
100
78.98
17.625
75.65
43.0
142.0
101
77.58
17.731
74.70
50.0
127.3
99
81.53
19.063
82.00
30.9
137.3
101
77.09
18.702
74.30
43.0
134.1
102
78.93
20.652
76.00
44.5
155.9
604
78.53
18.752
75.75
30.9
155.9
YM2008/00019/00
B2C109575
Height (cm) n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
<=17 years
18-64 years
>=65 years
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Table 6.9
Summary of Demographic Characteristics
Per Protocol
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
(N=583)
-----------------------------------------------------------------------------------------------------------Age (y)
n
98
97
98
98
93
99
583
Mean
39.9
44.3
42.3
41.2
43.0
43.8
42.4
SD
15.54
13.62
14.27
15.43
13.84
15.35
14.72
Median
42.0
45.0
44.0
43.5
46.0
45.0
44.0
Min.
12
15
16
12
12
13
12
Max.
68
74
80
72
70
73
80
7 (7%)
85 (87%)
6 (6%)
2 (2%)
88 (91%)
7 (7%)
2 (2%)
91 (93%)
5 (5%)
7 (7%)
84 (86%)
7 (7%)
3 (3%)
87 (94%)
3 (3%)
4 (4%)
87 (88%)
8 (8%)
25 (4%)
522 (90%)
36 (6%)
Sex
n
Female
Male
98
60 (61%)
38 (39%)
97
49 (51%)
48 (49%)
98
51 (52%)
47 (48%)
98
55 (56%)
43 (44%)
93
55 (59%)
38 (41%)
99
57 (58%)
42 (42%)
583
327 (56%)
256 (44%)
Ethnicity
n
Hispanic/Latino
Not Hispanic/Latino
98
9 (9%)
89 (91%)
97
13 (13%)
84 (87%)
98
10 (10%)
88 (90%)
98
12 (12%)
86 (88%)
93
12 (13%)
81 (87%)
99
21 (21%)
78 (79%)
583
77 (13%)
506 (87%)
98
165.6
9.36
165.0
142
188
97
169.6
11.32
171.0
135
200
98
167.0
9.66
165.5
149
193
98
168.4
10.14
169.5
140
191
93
167.5
9.90
167.0
150
193
99
167.6
10.00
168.0
147
198
583
167.6
10.11
167.0
135
200
Weight (kg) n
Mean
SD
Median
Min.
Max.
97
77.21
18.863
72.00
48.0
127.0
96
78.85
17.529
75.15
43.0
142.0
98
77.66
17.893
74.35
50.0
127.3
98
81.50
19.159
82.00
30.9
137.3
93
77.49
18.334
75.30
43.0
134.1
99
78.66
20.709
76.00
44.5
155.9
581
78.57
18.763
75.50
30.9
155.9
YM2008/00019/00
B2C109575
Height (cm) n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
158
<=17 years
18-64 years
>=65 years
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.10
Summary of Race and Racial Combinations
CONFIDENTIAL
159
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
African American/African
4
(4%)
11 (11%)
8
(8%)
12 (12%)
14 (14%)
8
(8%)
57
(9%)
Heritage
American Indian or
3
(3%)
2
(2%)
3
(3%)
2
(2%)
2
(2%)
1 (<1%)
13
(2%)
Alaska Native
Asian
11 (11%)
13 (13%)
11 (11%)
8
(8%)
9
(9%)
9
(9%)
61 (10%)
Central/South Asian
1 (<1%)
0
0
0
1 (<1%)
0
2 (<1%)
Heritage
Japanese/East Asian
10 (10%)
13 (13%)
11 (11%)
8
(8%)
8
(8%)
9
(9%)
59 (10%)
Heritage/South East
Asian Heritage
Native Hawaiian or other
0
0
1 (<1%)
0
0
0
1 (<1%)
Pacific Islander
White
81 (79%)
74 (73%)
77 (76%)
75 (75%)
75 (74%)
83 (81%) 465 (77%)
African American/African
0
1 (<1%)
0
0
0
0
1 (<1%)
Heritage & American
Indian or Alaska Native
African American/African
2
(2%)
0
0
0
0
0
2 (<1%)
Heritage & White
American Indian or
1 (<1%)
0
1 (<1%)
2
(2%)
1 (<1%)
1 (<1%)
6 (<1%)
Alaska Native & White
Asian & White
0
0
0
1
(1%)
0
0
1 (<1%)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.11
Summary of Race and Racial Combination Details
CONFIDENTIAL
160
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
African American/African
4
(4%)
11 (11%)
8
(8%)
12 (12%)
14 (14%)
8
(8%)
57
(9%)
Heritage
American Indian or
3
(3%)
2
(2%)
3
(3%)
2
(2%)
2
(2%)
1 (<1%)
13
(2%)
Alaska Native
Asian - Central/South
1 (<1%)
0
0
0
1 (<1%)
0
2 (<1%)
Asian Heritage
Asian - East Asian
5
(5%)
6
(6%)
5
(5%)
3
(3%)
2
(2%)
4
(4%)
25
(4%)
Heritage
Asian - Japanese
0
0
0
1
(1%)
0
0
1 (<1%)
Heritage
Asian - South East Asian
5
(5%)
7
(7%)
6
(6%)
4
(4%)
6
(6%)
5
(5%)
33
(5%)
Heritage
Asian - Mixed Race
0
0
0
0
0
0
0
Native Hawaiian or other
0
0
1 (<1%)
0
0
0
1 (<1%)
Pacific Islander
White - Arabic/North
0
2
(2%)
0
3
(3%)
0
0
5 (<1%)
African Heritage
White 81 (79%)
72 (71%)
77 (76%)
72 (72%)
75 (74%)
83 (81%) 460 (76%)
White/Caucasian/European
Heritage
White - Mixed Race
0
0
0
0
0
0
0
Mixed Race
3
(3%)
1 (<1%)
1 (<1%)
3
(3%)
1 (<1%)
1 (<1%)
10
(2%)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.12
Summary of History of Tobacco Use at Screening
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
Never smoked
86 (84%)
80 (79%)
82 (81%)
83 (83%)
87 (86%)
83 (81%)
501 (83%)
Former smoker
16 (16%)
21 (21%)
19 (19%)
17 (17%)
14 (14%)
19 (19%)
106 (17%)
CONFIDENTIAL
161
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.13
Summary of Duration of Asthma and Asthma History
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------------Duration of Asthma:
n
102
101
101
100
101
102
607
<6 months
0
0
0
0
0
0
0
>=6 months to <1 year
0
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
7 (1%)
>=1 year to <5 years
14 (14%)
11 (11%)
19 (19%)
16 (16%)
11 (11%)
16 (16%)
87 (14%)
>=5 years to <10 years
20 (20%)
13 (13%)
11 (11%)
12 (12%)
14 (14%)
20 (20%)
90 (15%)
>=10 years
68 (67%)
75 (74%)
70 (69%)
71 (71%)
74 (73%)
65 (64%) 423 (70%)
102
30 (29%)
72 (71%)
101
34 (34%)
67 (66%)
101
37 (37%)
64 (63%)
100
33 (33%)
67 (67%)
101
34 (34%)
67 (66%)
102
33 (32%)
69 (68%)
607
201 (33%)
406 (67%)
CONFIDENTIAL
162
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 6.14
Summary of Current Medical Conditions
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Classification
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Any Condition
84 (82%)
79 (78%)
76 (75%)
86 (86%)
78 (77%)
82 (80%)
485 (80%)
4
(4%)
20 (20%)
2
(2%)
23 (23%)
23 (23%)
2
(3%)
20 (20%)
(2%)
1 (<1%)
15 (15%)
23 (23%)
(3%)
26 (26%)
2
(2%)
20 (20%)
8
5
(8%)
(5%)
6 (6%)
1 (<1%)
5
3
(5%)
(3%)
8
6
(8%)
(6%)
(8%)
(7%)
(5%)
45 (44%)
38 (38%)
13 (13%)
16 (16%)
5
0
(5%)
(5%)
16 (16%)
0
(6%)
18 (18%)
1 (<1%)
22 (22%)
4
2
21 (21%)
21
(3%)
123 (20%)
8
(1%)
124 (20%)
(4%)
(2%)
6 (6%)
1 (<1%)
37
18
(6%)
(3%)
(9%)
15 (15%)
12 (12%)
56
(9%)
49 (49%)
36 (36%)
48 (47%)
257 (42%)
16 (16%)
73 (12%)
(7%)
12 (12%)
(9%)
8
0
(8%)
11 (11%)
0
10 (10%)
1 (<1%)
9
2
(9%)
(2%)
56 (9%)
3 (<1%)
14 (14%)
5 (5%)
18 (18%)
1 (<1%)
13 (13%)
3 (3%)
11 (11%)
3 (3%)
15 (15%)
2 (2%)
13 (13%)
6 (6%)
84 (14%)
20 (3%)
20 (20%)
15 (15%)
15 (15%)
15 (15%)
17 (17%)
25 (25%)
107 (18%)
10 (10%)
11 (11%)
5 (5%)
11 (11%)
10 (10%)
10 (10%)
8
5
(8%)
(5%)
4
8
(4%)
(8%)
12 (12%)
12 (12%)
49
57
(8%)
(9%)
YM2008/00019/00
B2C109575
13 (13%)
0
41 (41%)
CONFIDENTIAL
163
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 6.14
Summary of Current Medical Conditions
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Classification
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Gastrointestinal
16 (16%)
12 (12%)
12 (12%)
19 (19%)
13 (13%)
17 (17%)
89 (15%)
disorders
Hepatobiliary disorders
3 (3%)
3 (3%)
4 (4%)
1 (1%)
4 (4%)
4 (4%)
19 (3%)
Immune system disorders
9 (9%)
21 (21%)
12 (12%)
15 (15%)
13 (13%)
16 (16%)
86 (14%)
Metabolism and
7 (7%)
5 (5%)
5 (5%)
6 (6%)
9 (9%)
5 (5%)
37 (6%)
nutrition disorders
CONFIDENTIAL
164
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 6.15
Summary of Asthma Concomitant Medications Taken Pre-Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
102 (100%) 101 (100%) 101 (100%) 100 (100%) 101 (100%) 102 (100%)
(75%)
(42%)
(35%)
(23%)
71
37
48
16
(70%)
(37%)
(48%)
(16%)
78
40
35
24
(77%)
(40%)
(35%)
(24%)
77
44
36
24
(77%)
(44%)
(36%)
(24%)
80
43
35
18
(79%)
(43%)
(35%)
(18%)
77
33
36
18
(75%)
(32%)
(35%)
(18%)
9
11
7
4
1
4
5
4
2
1
1
3
0
(9%)
(11%)
(7%)
(4%)
(<1%)
(4%)
(5%)
(4%)
(2%)
(<1%)
(<1%)
(3%)
10
9
7
1
6
3
1
1
4
4
4
1
1
(10%)
(9%)
(7%)
(<1%)
(6%)
(3%)
(<1%)
(<1%)
(4%)
(4%)
(4%)
(<1%)
(<1%)
17
6
6
1
8
2
2
5
0
0
0
1
1
(17%)
(6%)
(6%)
(<1%)
(8%)
(2%)
(2%)
(5%)
11
14
4
7
5
2
4
1
1
1
1
0
0
(11%)
(14%)
(4%)
(7%)
(5%)
(2%)
(4%)
(1%)
(1%)
(1%)
(1%)
12
7
9
6
2
5
4
1
4
3
2
0
3
(12%)
(7%)
(9%)
(6%)
(2%)
(5%)
(4%)
(<1%)
(4%)
(3%)
(2%)
17
9
7
8
3
5
0
3
3
3
2
2
1
(17%)
(9%)
(7%)
(8%)
(3%)
(5%)
1
1
2
2
(<1%)
(<1%)
(2%)
(2%)
0
0
1
0
1
0
0
0
(<1%)
1
0
0
0
(1%)
2
1
0
0
(2%)
(<1%)
0
0
0
0
0
1
0
0
0
0
1
0
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
0
0
0
1
0
0
(<1%)
0
2
0
0
0
0
0
1
1
0
0
0
1
0
0
0
(1%)
(3%)
(2%)
(<1%)
(<1%)
0
0
0
0
0
0
(3%)
(3%)
(3%)
(2%)
(2%)
(<1%)
YM2008/00019/00
B2C109575
77
43
36
23
CONFIDENTIAL
165
SALBUTAMOL
FLUTICASONE PROPIONATE
BUDESONIDE
SALMETEROL XINAFOATE+FLUTICASONE
PROPIONATE
BECLOMETASONE DIPROPIONATE
BUDESONIDE+FORMOTEROL FUMARATE
FORMOTEROL FUMARATE
MOMETASONE FUROATE
SALMETEROL XINAFOATE
CICLESONIDE
MONTELUKAST SODIUM
BECLOMETASONE
FORMOTEROL
THEOPHYLLINE
TERBUTALINE SULFATE
FENOTEROL HYDROBROMIDE
FENOTEROL HYDROBROMIDE+IPRATROPIUM
BROMIDE
FLUTICASONE
LEVOSALBUTAMOL HYDROCHLORIDE
IPRATROPIUM BROMIDE
SALBUTAMOL SULFATE+IPRATROPIUM
BROMIDE
CETIRIZINE
CETIRIZINE HYDROCHLORIDE
CROMOGLICATE SODIUM+REPROTEROL
HYDROCHLORIDE
PIRBUTEROL ACETATE
PREDNISOLONE
SALBUTAMOL SULFATE
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 6.15
Summary of Asthma Concomitant Medications Taken Pre-Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------SALMETEROL
0
0
0
0
1 (<1%)
0
SALMETEROL+FLUTICASONE PROPIONATE
0
0
0
0
1 (<1%)
0
TIOTROPIUM BROMIDE
0
0
0
0
1 (<1%)
0
TRIAMCINOLONE ACETONIDE
0
1 (<1%)
0
0
0
0
CONFIDENTIAL
166
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.16
Summary of Asthma Concomitant Medications Taken During Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
101 (>99%) 101 (100%) 101 (100%) 100 (100%) 100 (>99%) 102 (100%)
43
36
9
4
4
2
4
1
0
0
0
0
1
0
(42%)
(35%)
(9%)
(4%)
(4%)
(2%)
(4%)
(<1%)
(<1%)
37
48
10
1
3
6
1
0
1
0
0
0
0
1
(37%)
(48%)
(10%)
(<1%)
(3%)
(6%)
(<1%)
(<1%)
(<1%)
41
35
17
1
2
2
5
1
0
0
1
1
0
0
(41%)
(35%)
(17%)
(<1%)
(2%)
(2%)
(5%)
(<1%)
(<1%)
(<1%)
44
35
10
7
2
4
1
1
0
1
0
0
0
0
(44%)
(35%)
(10%)
(7%)
(2%)
(4%)
(1%)
(1%)
(1%)
42
33
12
6
5
4
1
0
1
0
0
0
0
0
(42%)
(33%)
(12%)
(6%)
(5%)
(4%)
(<1%)
(<1%)
33
36
17
7
5
0
3
2
0
0
0
0
0
0
(32%)
(35%)
(17%)
(7%)
(5%)
(3%)
(2%)
CONFIDENTIAL
167
FLUTICASONE PROPIONATE
BUDESONIDE
BECLOMETASONE DIPROPIONATE
MOMETASONE FUROATE
CICLESONIDE
SALBUTAMOL
BECLOMETASONE
FLUTICASONE
PREDNISOLONE
FORMOTEROL FUMARATE
METHYLPREDNISOLONE
SALMETEROL XINAFOATE
THEOPHYLLINE
TRIAMCINOLONE ACETONIDE
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.17
Summary of Asthma Concomitant Medications Taken Post Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
101 (>99%) 101 (100%) 101 (100%) 100 (100%) 100 (>99%) 102 (100%)
(42%)
(35%)
(9%)
(4%)
(4%)
(2%)
(4%)
(2%)
(<1%)
37
48
10
1
3
5
1
1
1
1
2
1
0
0
0
0
0
0
0
0
0
1
0
0
0
(<1%)
(2%)
(<1%)
0
0
0
0
1
1
0
1
1
1
1
1
0
1
0
1
(<1%)
(37%)
(48%)
(10%)
(<1%)
(3%)
(5%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
41
35
17
1
2
1
4
1
2
(41%)
(35%)
(17%)
(<1%)
(2%)
(<1%)
(4%)
(<1%)
(2%)
44
35
10
7
2
3
1
1
1
(44%)
(35%)
(10%)
(7%)
(2%)
(3%)
(1%)
(1%)
(1%)
42
33
12
6
5
4
1
1
1
1
0
1
0
1
1
1
0
0
0
0
0
0
0
1
0
(<1%)
1
1
0
1
0
0
0
0
0
0
0
0
0
0
0
0
(1%)
(1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(1%)
(42%)
(33%)
(12%)
(6%)
(5%)
(4%)
(<1%)
(<1%)
(<1%)
33
36
17
7
5
0
3
0
0
(32%)
(35%)
(17%)
(7%)
(5%)
2
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
(2%)
(3%)
(<1%)
YM2008/00019/00
B2C109575
43
36
9
4
4
2
4
2
1
CONFIDENTIAL
168
FLUTICASONE PROPIONATE
BUDESONIDE
BECLOMETASONE DIPROPIONATE
MOMETASONE FUROATE
CICLESONIDE
SALBUTAMOL
BECLOMETASONE
MONTELUKAST SODIUM
SALMETEROL XINAFOATE+FLUTICASONE
PROPIONATE
FLUTICASONE
BUDESONIDE+FORMOTEROL FUMARATE
CLARITHROMYCIN
FORMOTEROL FUMARATE
METHYLPREDNISOLONE
PREDNISOLONE
AMBROXOL HYDROCHLORIDE
BEPOTASTINE
CARBOCISTEINE+SOBREROL
DEFLAZACORT
DEXAMETHASONE SODIUM PHOSPHATE
FEXOFENADINE HYDROCHLORIDE
PREDNISONE
ROXITHROMYCIN
SALMETEROL XINAFOATE
TRIAMCINOLONE ACETONIDE
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
68 (67%)
58 (57%)
48 (48%)
68 (68%)
62 (61%)
58 (57%)
31
4
5
2
4
1
2
1
2
1
1
0
2
1
1
0
(30%)
(4%)
(5%)
(2%)
(4%)
(<1%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
28
4
6
1
2
2
2
1
1
2
1
0
1
2
3
1
(28%)
(4%)
(6%)
(<1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(2%)
(3%)
(<1%)
22
11
1
3
4
2
1
2
2
1
2
1
1
0
1
1
(22%)
(11%)
(<1%)
(3%)
(4%)
(2%)
(<1%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
33 (33%)
6 (6%)
4 (4%)
8 (8%)
0
1 (1%)
1 (1%)
2 (2%)
1 (1%)
1 (1%)
0
4 (4%)
2 (2%)
0
1 (1%)
2 (2%)
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
1 (<1%)
2 (2%)
1 (<1%)
0
1
0
0
1
1
2 (2%)
1 (<1%)
0
0
0
0
0
1
1 (<1%)
0
0
0
1 (<1%)
0
0
0
(1%)
(23%)
(4%)
(4%)
(2%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
29
4
5
3
3
4
1
2
2
2
2
1
1
2
0
2
(28%)
(4%)
(5%)
(3%)
(3%)
(4%)
(<1%)
(2%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(2%)
(1%)
(1%)
0
1 (<1%)
0
0
0
2 (2%)
0
1 (<1%)
2 (2%)
0
(1%)
1 (<1%)
1 (<1%)
0
0
0
2
0
0
(2%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
0
2 (2%)
1 (<1%)
0
1 (<1%)
23
4
4
0
2
3
2
1
0
0
1
1
0
1
0
0
CONFIDENTIAL
169
RESPIRATORY SYSTEM
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
LORATADINE
AZELASTINE HYDROCHLORIDE
CETIRIZINE HYDROCHLORIDE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
PHENIRAMINE
BROMHEXINE
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
FEXOFENADINE HYDROCHLORIDE
FLUTICASONE FUROATE
PSEUDOEPHEDRINE
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
COUGH COLD PREPARATIONS NOS
DESLORATADINE
LEVOCETIRIZINE HYDROCHLORIDE
PSEUDOEPHEDRINE HYDROCHLORIDE
DIPHENHYDRAMINE
HYDROCHLORIDE+PARACETAMOL
MONTELUKAST SODIUM
PSEUDOEPHEDRINE
SULFATE+LORATADINE
ACETYLCYSTEINE
CETIRIZINE
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
170
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CHLORPHENAMINE
0
1 (<1%)
0
0
1 (<1%)
0
CHLORPHENAMINE MALEATE
0
0
1 (<1%)
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
MEQUITAZINE
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
0
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL SINUS (NOS)
0
0
0
1 (1%)
0
1 (<1%)
ASCORBIC
0
1 (<1%)
0
0
0
0
ACID+PARACETAMOL+CHLORPHENAMINE
MALEATE+PHENYLPROPANOLAMINE
HYDROCHLORIDE
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BUCKLEY'S MIXTURE (NOS)
0
1 (<1%)
0
0
0
0
CARDIOSPERMUM+GALPHIMIA
0
0
0
0
1 (<1%)
0
GLAUCA+LUFFA OPERCULATA
DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
TANNATE+MEPYRAMINE
TANNATE+PHENYLEPHRINE TANNATE
DIMENHYDRINATE
0
1 (<1%)
0
0
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
EBASTINE
1 (<1%)
0
0
0
0
0
FLUNISOLIDE
0
0
0
0
1 (<1%)
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
28 (27%)
8 (8%)
3 (3%)
2 (2%)
24 (24%)
5 (5%)
4 (4%)
3 (3%)
20 (20%)
5 (5%)
2 (2%)
3 (3%)
32 (32%)
7 (7%)
5 (5%)
2 (2%)
28 (28%)
5 (5%)
6 (6%)
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
27 (26%)
3 (3%)
8 (8%)
0
YM2008/00019/00
B2C109575
CONFIDENTIAL
171
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------GUAIFENESIN+DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
HYDROBROMIDE
GUAIFENESIN+PSEUDOEPHEDRINE
0
1 (<1%)
0
0
0
0
HYDROCHLORIDE
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
NEOZEP NOS
0
0
0
0
1 (<1%)
0
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+HYDROCODONE
0
0
0
0
0
1 (<1%)
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PROMETHAZINE
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
SODIUM BICARBONATE+SODIUM
1 (<1%)
0
0
0
0
0
CHLORIDE
XYLOMETAZOLINE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
172
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
OMEPRAZOLE
3 (3%)
0
1 (<1%)
1 (1%)
3 (3%)
1 (<1%)
ESOMEPRAZOLE MAGNESIUM
2 (2%)
1 (<1%)
0
3 (3%)
1 (<1%)
1 (<1%)
LANSOPRAZOLE
1 (<1%)
0
0
1 (1%)
4 (4%)
2 (2%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
METFORMIN
0
1 (<1%)
1 (<1%)
1 (1%)
2 (2%)
2 (2%)
MINERALS NOS+VITAMINS NOS
4 (4%)
0
0
0
2 (2%)
1 (<1%)
RANITIDINE HYDROCHLORIDE
0
1 (<1%)
2 (2%)
2 (2%)
1 (<1%)
1 (<1%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
ASCORBIC ACID
0
1 (<1%)
0
1 (1%)
1 (<1%)
2 (2%)
CALCIUM
1 (<1%)
2 (2%)
0
0
1 (<1%)
1 (<1%)
VITAMIN D NOS
0
1 (<1%)
3 (3%)
0
0
1 (<1%)
BISMUTH SUBSALICYLATE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
DOCUSATE SODIUM
2 (2%)
0
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FAMOTIDINE
1 (<1%)
0
0
0
0
1 (<1%)
GLIBENCLAMIDE
0
1 (<1%)
1 (<1%)
0
0
0
GLIMEPIRIDE
0
0
0
1 (1%)
0
1 (<1%)
INSULIN ASPART
0
1 (<1%)
0
0
0
1 (<1%)
INSULIN GLARGINE
0
1 (<1%)
0
0
0
1 (<1%)
METFORMIN HYDROCHLORIDE
0
0
0
1 (1%)
0
1 (<1%)
PANTOPRAZOLE SODIUM
1 (<1%)
0
0
0
1 (<1%)
0
RABEPRAZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
0
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ALMAGATE
0
0
0
1 (1%)
0
0
ALUMINIUM HYDROXIDE GEL+MAGNESIUM
1 (<1%)
0
0
0
0
0
HYDROXIDE
ALUMINIUM HYDROXIDE+MAGNESIUM
0
0
0
0
0
1 (<1%)
HYDROXIDE+DIMETICONE, ACTIVATED
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
173
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ALUMINIUM PHOSPHATE+AGAR+PECTIN
0
0
0
0
0
1 (<1%)
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CIMETIDINE
0
1 (<1%)
0
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DIMENHYDRINATE
0
1 (<1%)
0
0
0
0
DIMETICONE, ACTIVATED
0
0
0
0
1 (<1%)
0
DOMPERIDONE
0
0
1 (<1%)
0
0
0
ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
ITOPRIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
LOPERAMIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
MISOPROSTOL
0
0
0
0
0
1 (<1%)
NYSTATIN
0
0
0
0
0
1 (<1%)
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PREDNISONE
1 (<1%)
0
0
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
29 (28%)
13 (13%)
9 (9%)
3 (3%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
30 (30%)
13 (13%)
12 (12%)
4 (4%)
2 (2%)
1
0
1
0
1
1
1
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
16 (16%)
8 (8%)
6 (6%)
2 (2%)
0
1 (<1%)
0
0
0
1 (<1%)
0
1 (<1%)
31 (31%)
8 (8%)
8 (8%)
5 (5%)
3 (3%)
1
1
2
3
1
0
0
(1%)
(1%)
(2%)
(3%)
(1%)
27 (27%)
13 (13%)
5 (5%)
6 (6%)
1 (<1%)
26 (25%)
9 (9%)
2 (2%)
8 (8%)
0
2 (2%)
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID
ACETYLSALICYLIC
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
CLONAZEPAM
ESCITALOPRAM OXALATE
FLUOXETINE HYDROCHLORIDE
SERTRALINE HYDROCHLORIDE
BUPROPION HYDROCHLORIDE
CITALOPRAM HYDROBROMIDE
CONFIDENTIAL
174
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0
SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM BICARBONATE+SODIUM
1 (<1%)
0
0
0
0
0
CHLORIDE
THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
175
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
0
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
EXCEDRIN (NOS)
0
0
0
0
0
3 (3%)
HYDROXYZINE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
SUMATRIPTAN
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
0
1 (<1%)
0
0
0
1 (<1%)
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
METAMIZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
ASCORBIC
0
1 (<1%)
0
0
0
0
ACID+PARACETAMOL+CHLORPHENAMINE
MALEATE+PHENYLPROPANOLAMINE
HYDROCHLORIDE
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
176
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+CAFFEINE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LORAZEPAM
0
1 (<1%)
0
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
ORPHENADRINE CITRATE
1 (<1%)
0
0
0
0
0
OXIRACETAM
0
0
0
1 (1%)
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+HYDROCODONE
0
0
0
0
0
1 (<1%)
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
177
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
Any medication
23 (23%)
20 (20%)
21 (21%)
20 (20%)
20 (20%)
16 (16%)
ENALAPRIL
2 (2%)
0
2 (2%)
3 (3%)
3 (3%)
1 (<1%)
HYDROCHLOROTHIAZIDE
2 (2%)
5 (5%)
1 (<1%)
0
2 (2%)
1 (<1%)
AMLODIPINE BESILATE
1 (<1%)
2 (2%)
1 (<1%)
3 (3%)
1 (<1%)
2 (2%)
SIMVASTATIN
1 (<1%)
2 (2%)
0
0
2 (2%)
2 (2%)
VERAPAMIL
3 (3%)
1 (<1%)
0
1 (1%)
2 (2%)
0
AMLODIPINE
1 (<1%)
1 (<1%)
0
0
4 (4%)
0
VERAPAMIL HYDROCHLORIDE
1 (<1%)
0
1 (<1%)
3 (3%)
1 (<1%)
0
ENALAPRIL MALEATE
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
LISINOPRIL
0
0
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
PERINDOPRIL
0
1 (<1%)
0
0
4 (4%)
0
ATORVASTATIN CALCIUM
1 (<1%)
0
0
1 (1%)
0
2 (2%)
HYDROCHLOROTHIAZIDE+LOSARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
POTASSIUM
INDAPAMIDE
0
0
1 (<1%)
1 (1%)
0
2 (2%)
VALSARTAN
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
FISH OIL
0
0
2 (2%)
0
0
1 (<1%)
FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
IRBESARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
LOSARTAN POTASSIUM
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
178
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACETAZOLAMIDE
0
0
0
1 (1%)
0
0
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CAPTOPRIL
1 (<1%)
0
0
0
0
0
CHLORTALIDONE+ATENOLOL
0
0
0
1 (1%)
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LOVASTATIN
0
0
0
0
1 (<1%)
0
METOPROLOL SUCCINATE
0
1 (<1%)
0
0
0
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0
17
4
5
2
1
1
0
2
0
1
(17%)
(4%)
(5%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(19%)
(4%)
(6%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
0
2 (2%)
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
18
11
1
1
2
2
1
1
1
0
(18%)
(11%)
(<1%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
25 (25%)
6 (6%)
4 (4%)
1 (1%)
2 (2%)
0
4 (4%)
2 (2%)
0
0
1
0
0
1
1
1
1
1
0
1
0
0
0
0
0
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
14
4
4
2
1
1
1
0
1
0
(14%)
(4%)
(4%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
17
4
5
1
2
2
1
1
0
1
(17%)
(4%)
(5%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
YM2008/00019/00
B2C109575
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
19
4
6
2
1
1
0
1
1
0
CONFIDENTIAL
179
DERMATOLOGICALS
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
HYDROCORTISONE
ETHINYLOESTRADIOL+CYPROTERONE
ACETATE
TOCOPHEROL
TRIAMCINOLONE
BETAMETHASONE DIPROPIONATE
BETAMETHASONE+CALCIPOTRIOL
CLINDAMYCIN PHOSPHATE+TRETINOIN
CLINDAMYCIN+BENZOYL PEROXIDE
DESOXIMETASONE
DIPHENHYDRAMINE
DIPHENHYDRAMINE HYDROCHLORIDE
FLUCONAZOLE
FLUTICASONE
HYALURONIC ACID
NYSTATIN
PREDNISOLONE
PROMETHAZINE
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0
25
9
3
3
4
1
0
0
1
1
(25%)
(9%)
(3%)
(3%)
(4%)
(<1%)
2
0
0
(2%)
(<1%)
(<1%)
18
12
2
0
0
1
1
0
0
0
(18%)
(12%)
(2%)
(<1%)
(<1%)
12 (12%)
6 (6%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
18 (18%)
8 (8%)
0
2 (2%)
0
1 (1%)
1 (1%)
1 (1%)
1 (1%)
0
15
5
1
2
0
1
0
2
0
1
(15%)
(5%)
(<1%)
(2%)
(<1%)
16
2
4
1
2
0
1
0
1
1
0
0
1 (<1%)
0
0
0
(<1%)
(2%)
(16%)
(2%)
(4%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
0
1 (<1%)
0
0
0
1
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
2 (2%)
1 (<1%)
0
0
0
0
0
0
0
0
1
0
0
2 (2%)
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
(1%)
(1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
1 (<1%)
2 (2%)
0
CONFIDENTIAL
180
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
17 (17%)
9 (9%)
3 (3%)
2 (2%)
0
1 (<1%)
1 (<1%)
0
0
0
20
12
4
1
1
1
1
2
0
1
(20%)
(12%)
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
12
6
2
0
1
0
1
1
0
1
(12%)
(6%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
18 (18%)
8 (8%)
5 (5%)
0
1 (1%)
1 (1%)
0
0
0
0
16 (16%)
5 (5%)
6 (6%)
0
0
1 (<1%)
0
0
1 (<1%)
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
12
2
8
1
1
0
0
0
1
0
(12%)
(2%)
(8%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
ALENDRONATE SODIUM
DICLOFENAC
NAPROXEN SODIUM
DICLOFENAC SODIUM
NAPROXEN
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE
CONFIDENTIAL
181
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)
ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
MISOPROSTOL
0
0
0
0
0
1 (<1%)
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
NYSTATIN
0
0
0
0
0
1 (<1%)
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0
TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
10 (10%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0
9
3
1
1
1
1
2
(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
9 (9%)
3 (3%)
2 (2%)
1 (<1%)
2 (2%)
1 (<1%)
0
7
5
0
2
0
0
0
(7%)
(5%)
(2%)
3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
8 (8%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
YM2008/00019/00
B2C109575
CONFIDENTIAL
182
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
CAPSAICIN+DIPROPYLENE GLYCOL
0
0
0
0
0
1 (<1%)
SALICYLATE
CELECOXIB
0
0
0
1 (1%)
0
0
CHONDROITIN SULFATE SODIUM
0
0
0
1 (1%)
0
0
COLCHICUM AUTUMNALE
0
1 (<1%)
0
0
0
0
COLECALCIFEROL+ALENDRONIC ACID
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
0
0
0
0
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
KETOPROFEN
0
0
1 (<1%)
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
MELOXICAM
0
0
0
0
1 (<1%)
0
METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
ORPHENADRINE CITRATE
1 (<1%)
0
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
LIOTHYRONINE
0
0
1 (<1%)
0
0
0
LIOTHYRONINE SODIUM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PREDNISONE
1 (<1%)
0
0
0
0
0
THYROID
0
0
1 (<1%)
0
0
0
6 (6%)
4 (4%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
0
5
2
1
1
1
0
0
0
0
0
0
0
0
1
(5%)
(2%)
(<1%)
(<1%)
(<1%)
SENSORY ORGANS
Any medication
TRIAMCINOLONE ACETONIDE
DICLOFENAC
DICLOFENAC SODIUM
HYDROCORTISONE
ACETYLCYSTEINE
EPINEPHRINE
8 (8%)
2 (2%)
0
1 (<1%)
0
1 (<1%)
1 (<1%)
8
1
1
1
1
0
0
8
1
1
1
1
1
1
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
10 (10%)
5 (5%)
1 (1%)
0
0
1 (1%)
0
1 (1%)
0
0
0
1 (1%)
1 (1%)
0
7
2
1
0
0
0
0
(7%)
(2%)
(1%)
8 (8%)
6 (6%)
0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0
9 (9%)
8 (8%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
CONFIDENTIAL
5 (5%)
3 (3%)
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
3 (3%)
1 (<1%)
1 (<1%)
0
0
0
0
YM2008/00019/00
B2C109575
183
Note: A medication may be included in more than one ATC Level category and appear more than once.
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
184
3 (3%)
1 (<1%)
0
0
2 (2%)
0
4 (4%)
2 (2%)
1 (<1%)
0
1 (<1%)
0
2
2
0
0
0
0
(2%)
(2%)
2
0
1
1
0
0
(2%)
VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
ACETYLCYSTEINE
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM
4 (4%)
0
1 (<1%)
1 (<1%)
0
0
2 (2%)
1 (<1%)
0
0
1 (<1%)
0
2 (2%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
3
1
0
0
0
1
(3%)
(1%)
(1%)
(1%)
(1%)
2 (2%)
0
0
2 (2%)
0
1 (<1%)
3 (3%)
2 (2%)
1 (<1%)
0
0
0
2 (2%)
0
1 (<1%)
0
0
0
2 (2%)
1 (<1%)
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
OLOPATADINE HYDROCHLORIDE
0
1 (<1%)
0
1 (1%)
0
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACETAZOLAMIDE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
XYLOMETAZOLINE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
0
0
0
0
1
1
1
ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
1 (<1%)
0
0
0
0
0
0
(3%)
(1%)
(1%)
(1%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
CONFIDENTIAL
185
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ALOE
0
0
0
1 (1%)
0
0
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
0
0
0
0
0
1 (<1%)
CHONDROITIN SULFATE SODIUM
0
0
0
1 (1%)
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DOCOSAHEXANOIC
0
0
0
0
1 (<1%)
0
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MEDICATION UNKNOWN
0
0
0
0
1 (<1%)
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
VITIS VINIFERA
1 (<1%)
0
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 18
Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PERMETHRIN
0
0
0
0
1 (<1%)
0
CONFIDENTIAL
186
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
72 (71%)
64 (63%)
58 (57%)
72 (72%)
63 (62%)
67 (66%)
34 (33%)
17 (17%)
11 (11%)
4 (4%)
0
(37%)
(16%)
(16%)
(6%)
(<1%)
29 (29%)
16 (16%)
9 (9%)
2 (2%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
0
1 (<1%)
1
1
1
1
0
1
0
1
0
0
0
1
0
1
0
0
1
1
1
1
1
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
2
1
3
1
0
0
0
0
1
1
(<1%)
(<1%)
(<1%)
(<1%)
37
16
16
6
1
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
32 (32%)
10 (10%)
7 (7%)
3 (3%)
3 (3%)
34 (34%)
17 (17%)
11 (11%)
6 (6%)
0
32 (31%)
13 (13%)
7 (7%)
8 (8%)
0
(1%)
(1%)
(1%)
1 (<1%)
0
0
0
1 (<1%)
0
(2%)
(1%)
(3%)
(1%)
0
0
0
0
0
1
1
1
0
1
0
3
0
1
1
0
1
1
0
0
(1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
1
1 (<1%)
0
0
0
1 (<1%)
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
(1%)
CONFIDENTIAL
187
NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID
ACETYLSALICYLIC
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
CLONAZEPAM
DIPHENHYDRAMINE
HYDROCHLORIDE+PARACETAMOL
ESCITALOPRAM OXALATE
EXCEDRIN (NOS)
FLUOXETINE HYDROCHLORIDE
SERTRALINE HYDROCHLORIDE
BUPROPION HYDROCHLORIDE
CITALOPRAM HYDROBROMIDE
DIAZEPAM
HYDROXYZINE
SUMATRIPTAN
ACETYLSALICYLIC
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
CYCLOBENZAPRINE HYDROCHLORIDE
ERGOTAMINE TARTRATE+CAFFEINE
KETOROLAC TROMETAMOL
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
188
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------METAMIZOLE SODIUM
0
0
1 (<1%)
1 (1%)
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
PROCAINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
0
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAMADOL
0
0
1 (<1%)
0
1 (<1%)
0
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC ACID+CALCIUM
0
0
1 (<1%)
0
0
0
CARBONATE
ACETYLSALICYLIC ACID+PARACETAMOL
0
0
0
1 (1%)
0
0
ACETYLSALICYLIC ACID+SODIUM
0
0
0
1 (1%)
0
0
BICARBONATE+CITRIC ACID
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
ACETYLSALICYLIC
0
0
0
0
0
1 (<1%)
ACID+PHENACETIN+CAFFEINE+CITRIC
ACID+THEOBROMA CACAO
CAFFEINE
1 (<1%)
0
0
0
0
0
CHOLINE SALICYLATE
0
0
1 (<1%)
0
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL
EPINEPHRINE+ARTICAINE
0
0
0
0
1 (<1%)
0
HYDROCHLORIDE
ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
189
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FIORINAL NOS
0
1 (<1%)
0
0
0
0
FLUNARIZINE
0
0
0
0
1 (<1%)
0
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
LORAZEPAM
0
0
1 (<1%)
0
0
0
MED-LEMON (NOS)
1 (<1%)
0
0
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
OXYCODONE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
PARACETAMOL+CAFFEINE+BUTALBITAL
0
0
0
0
1 (<1%)
0
PARACETAMOL+CAFFEINE+MEPYRAMINE
0
1 (<1%)
0
0
0
0
MALEATE
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
190
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
Any medication
35 (34%)
29 (29%)
22 (22%)
32 (32%)
24 (24%)
28 (27%)
FLUTICASONE PROPIONATE
4 (4%)
4 (4%)
11 (11%)
6 (6%)
4 (4%)
3 (3%)
MOMETASONE FUROATE
5 (5%)
6 (6%)
1 (<1%)
4 (4%)
3 (3%)
4 (4%)
LORATADINE
2 (2%)
2 (2%)
3 (3%)
7 (7%)
0
2 (2%)
BENADRYL (NOS)
2 (2%)
1 (<1%)
3 (3%)
0
1 (<1%)
3 (3%)
BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
PHENIRAMINE
2 (2%)
1 (<1%)
2 (2%)
1 (1%)
0
2 (2%)
PSEUDOEPHEDRINE HYDROCHLORIDE
1 (<1%)
2 (2%)
1 (<1%)
0
0
4 (4%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
FLUTICASONE FUROATE
1 (<1%)
3 (3%)
1 (<1%)
1 (1%)
0
0
AZELASTINE HYDROCHLORIDE
2 (2%)
2 (2%)
0
0
1 (<1%)
0
CETIRIZINE HYDROCHLORIDE
1 (<1%)
2 (2%)
0
0
1 (<1%)
1 (<1%)
PSEUDOEPHEDRINE
0
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
0
0
0
1 (<1%)
3 (3%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
BROMHEXINE
1 (<1%)
0
1 (<1%)
1 (1%)
0
1 (<1%)
COUGH COLD PREPARATIONS NOS
0
2 (2%)
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
FEXOFENADINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
GUAIFENESIN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
PARACETAMOL+DEXTROMETHORPHAN
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE
SUCCINATE
CHLORPHENAMINE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
191
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CHLORPHENAMINE MALEATE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
1 (<1%)
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
TYLENOL SINUS (NOS)
0
0
1 (<1%)
1 (1%)
0
1 (<1%)
DESLORATADINE
1 (<1%)
0
0
0
1 (<1%)
0
DIMENHYDRINATE
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FLUNISOLIDE
0
0
0
1 (1%)
1 (<1%)
0
GUAIFENESIN+DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
1 (<1%)
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
GUAIFENESIN+PSEUDOEPHEDRINE
1 (<1%)
0
0
0
0
1 (<1%)
HYDROCHLORIDE
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
LEVOMENTHOL+EUCALYPTUS GLOBULUS
2 (2%)
0
0
0
0
0
PARACETAMOL+DEXTROMETHORPHAN
0
1 (<1%)
0
0
1 (<1%)
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
1 (<1%)
0
0
0
0
SULFATE+LORATADINE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL COLD NOS
0
1 (<1%)
0
0
1 (<1%)
0
XYLOMETAZOLINE HYDROCHLORIDE
0
1 (<1%)
0
1 (1%)
0
0
BENZALKONIUM
1 (<1%)
0
0
0
0
0
CHLORIDE+THYMOL+LEVOMENTHOL+EUCAL
YPTUS GLOBULUS OIL
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
192
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CARDIOSPERMUM+GALPHIMIA
0
0
0
0
1 (<1%)
0
GLAUCA+LUFFA OPERCULATA
CETIRIZINE
0
0
0
0
1 (<1%)
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
0
DIABETIC TUSSIN (NOS)
0
1 (<1%)
0
0
0
0
DICHLOROBENZYL
0
1 (<1%)
0
0
0
0
ALCOHOL+AMYLMETACRESOL
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
EBASTINE
1 (<1%)
0
0
0
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN+DEXTROMETHORPHAN
0
1 (<1%)
0
0
0
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
LIDOCAINE
0
1 (<1%)
0
0
0
0
MED-LEMON (NOS)
1 (<1%)
0
0
0
0
0
MONTELUKAST SODIUM
1 (<1%)
0
0
0
0
0
NEOZEP NOS
0
0
0
0
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE+PHENYL
0
0
0
0
1 (<1%)
0
EPHRINE HYDROCHLORIDE
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
POTASSIUM
0
1 (<1%)
0
0
0
0
BICARBONATE+CAMPHOR+LEVOMENTHOL+A
MMONIUM CARBONATE
PROMETHAZINE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
30
8
4
2
3
2
2
1
0
1
0
4
0
2
0
1
(29%)
(8%)
(4%)
(2%)
(3%)
(2%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(<1%)
25
5
6
3
0
2
1
0
1
1
1
0
0
1
1
2
(25%)
(5%)
(6%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
21
5
2
3
2
1
0
0
3
2
1
0
1
1
0
0
(21%)
(5%)
(2%)
(3%)
(2%)
(<1%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
31 (31%)
7 (7%)
3 (3%)
2 (2%)
1 (1%)
1 (1%)
3 (3%)
1 (1%)
2 (2%)
0
1 (1%)
0
4 (4%)
2 (2%)
1 (1%)
0
28
5
6
0
3
2
1
4
1
1
2
2
1
0
1
1
(28%)
(5%)
(6%)
(3%)
(2%)
(<1%)
(4%)
(<1%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
30
3
8
0
1
1
1
2
1
2
2
1
1
1
2
1
(29%)
(3%)
(8%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
YM2008/00019/00
B2C109575
CONFIDENTIAL
193
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
PSEUDOEPHEDRINE+TRIPROLIDINE
0
0
0
0
0
1 (<1%)
PSEUDOEPHEDRINE
0
0
0
1 (1%)
0
0
HYDROCHLORIDE+IBUPROFEN
ROBITUSSIN (NOS)
0
0
0
0
1 (<1%)
0
TETRYZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
THIETHYLPERAZINE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+THYMOL+AZULENE+EUCALYP
1 (<1%)
0
0
0
0
0
TUS GLOBULUS OIL+OLEUM PINI
SYLVESTRIS+MENTHA PIPERATA OIL
VICKS VAPORUB NOS
1 (<1%)
0
0
0
0
0
ZIPEPROL HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
194
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------VITAMIN D NOS
0
1 (<1%)
3 (3%)
0
0
1 (<1%)
LOPERAMIDE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
1 (1%)
0
1 (<1%)
DOCUSATE SODIUM
2 (2%)
0
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
RABEPRAZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
DIMENHYDRINATE
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FAMOTIDINE
1 (<1%)
0
0
0
0
1 (<1%)
GLIBENCLAMIDE
0
1 (<1%)
1 (<1%)
0
0
0
GLIMEPIRIDE
0
0
0
1 (1%)
0
1 (<1%)
INSULIN ASPART
0
1 (<1%)
0
0
0
1 (<1%)
INSULIN GLARGINE
0
1 (<1%)
0
0
0
1 (<1%)
METFORMIN HYDROCHLORIDE
0
0
0
1 (1%)
0
1 (<1%)
PANTOPRAZOLE SODIUM
1 (<1%)
0
0
0
1 (<1%)
0
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACETYLSALICYLIC ACID+SODIUM
0
0
0
1 (1%)
0
0
BICARBONATE+CITRIC ACID
ACTIVATED CHARCOAL
1 (<1%)
0
0
0
0
0
ALUMINIUM HYDROXIDE+MAGNESIUM
0
0
0
0
0
1 (<1%)
HYDROXIDE+DIMETICONE, ACTIVATED
ANTACIL NOS
0
0
0
0
0
1 (<1%)
BACILLUS LICHENIFORMIS
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAMOMILE
1 (<1%)
0
0
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIMETICONE, ACTIVATED
0
0
0
0
1 (<1%)
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
195
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
HYOSCINE BUTYLBROMIDE
0
0
1 (<1%)
0
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
ITOPRIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MANNITOL
1 (<1%)
0
0
0
0
0
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
PARGEVERINE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
PHLOROGLUCINOL+TRIMETHYLPHLOROGLU
1 (<1%)
0
0
0
0
0
CINOL
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0
SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM
0
0
1 (<1%)
0
0
0
BICARBONATE+THIAMINE+CALCIUM
CARBONATE+AMYLASE+SCOPOLIA
CARNIOLICA+SYZYGIUM
AROMATICUM+FOENICULUM VULGARE OIL
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
196
23
2
2
1
1
3
1
1
1
0
0
1
0
(23%)
(2%)
(2%)
(<1%)
(<1%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
0
0
1 (<1%)
1 (<1%)
0
24
0
4
2
2
1
1
0
1
0
1
0
1
(24%)
(21%)
(2%)
(<1%)
(<1%)
(<1%)
21
2
1
1
0
0
0
1
1
2
0
0
1
0
2 (2%)
1 (<1%)
1 (<1%)
0
1
1
1
1
2
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
19 (19%)
3 (3%)
1 (1%)
3 (3%)
0
1 (1%)
0
3 (3%)
0
1 (1%)
0
1 (1%)
1 (1%)
1
1
1
1
0
(1%)
(1%)
(1%)
(1%)
21
3
2
1
2
2
4
1
1
1
4
0
0
(21%)
(3%)
(2%)
(<1%)
(2%)
(2%)
(4%)
(<1%)
(<1%)
(<1%)
(4%)
0
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
16
1
1
2
2
0
0
0
1
1
0
2
1
(16%)
(<1%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
2 (2%)
0
0
0
1 (<1%)
YM2008/00019/00
B2C109575
CARDIOVASCULAR SYSTEM
Any medication
ENALAPRIL
HYDROCHLOROTHIAZIDE
AMLODIPINE BESILATE
SIMVASTATIN
VERAPAMIL
AMLODIPINE
VERAPAMIL HYDROCHLORIDE
ENALAPRIL MALEATE
LISINOPRIL
PERINDOPRIL
ATORVASTATIN CALCIUM
HYDROCHLOROTHIAZIDE+LOSARTAN
POTASSIUM
INDAPAMIDE
IRBESARTAN
LOSARTAN POTASSIUM
VALSARTAN
FISH OIL
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
TRIMEBUTINE MALEATE
1 (<1%)
0
0
0
0
0
TRIMETHOBENZAMIDE
0
1 (<1%)
0
0
0
0
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
197
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)
PROCAINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
0
0
0
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CAPTOPRIL
1 (<1%)
0
0
0
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
FLUNARIZINE
0
0
0
0
1 (<1%)
0
FUROSEMIDE
0
0
0
0
0
1 (<1%)
HEPARIN SODIUM
0
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
26
11
3
3
4
1
0
0
0
1
(25%)
(11%)
(3%)
(3%)
(4%)
(<1%)
(<1%)
22
16
2
0
0
1
2
1
0
0
(22%)
(16%)
(2%)
(<1%)
(2%)
(<1%)
16 (16%)
9 (9%)
1 (<1%)
1 (<1%)
0
0
2 (2%)
0
0
0
18 (18%)
7 (7%)
0
2 (2%)
0
1 (1%)
0
1 (1%)
1 (1%)
1 (1%)
20
11
1
2
0
1
0
0
2
0
(20%)
(11%)
(<1%)
(2%)
(<1%)
(2%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
18
7
4
1
2
1
0
1
0
1
(18%)
(7%)
(4%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
CONFIDENTIAL
198
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LIDOCAINE
0
1 (<1%)
0
0
0
0
LOVASTATIN
0
0
0
0
1 (<1%)
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
NIFEDIPINE
0
1 (<1%)
0
0
0
0
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0
TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
199
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ETHINYLOESTRADIOL+NORETHISTERONE
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
ACETATE
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
ETHINYLOESTRADIOL+GESTODENE
0
0
0
0
2 (2%)
0
ETHINYLOESTRADIOL+NORETHISTERONE
0
0
2 (2%)
0
0
0
CYPROTERONE ACETATE
0
1 (<1%)
0
0
0
0
DESOGESTREL
0
0
0
1 (1%)
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
ESTRADIOL+DYDROGESTERONE
0
1 (<1%)
0
0
0
0
ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)
ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LEVONORGESTREL
0
0
1 (<1%)
0
0
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0
20
11
4
1
1
2
0
1
0
0
0
0
0
(20%)
(11%)
(4%)
(<1%)
(<1%)
(2%)
(<1%)
(26%)
(16%)
(6%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
17
9
2
1
0
0
2
1
0
1
1
1
0
(17%)
(9%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
0
1 (<1%)
0
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
15 (15%)
7 (7%)
3 (3%)
2 (2%)
1 (1%)
0
0
0
0
0
0
1 (1%)
0
1
0
1
0
0
0
0
0
0
0
0
0
0
(1%)
(1%)
23
11
6
1
1
0
0
0
1
0
1
0
0
(23%)
(11%)
(6%)
(<1%)
(<1%)
(<1%)
(<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
16
7
8
1
1
1
0
0
1
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
(16%)
(7%)
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
26
16
6
1
1
1
2
1
0
1
0
0
0
CONFIDENTIAL
200
MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
DICLOFENAC
NAPROXEN SODIUM
ALENDRONATE SODIUM
NAPROXEN
DICLOFENAC SODIUM
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE
CYCLOBENZAPRINE HYDROCHLORIDE
KETOROLAC TROMETAMOL
CAPSAICIN+DIPROPYLENE GLYCOL
SALICYLATE
CELECOXIB
CHLORZOXAZONE
CHONDROITIN SULFATE SODIUM
COLCHICUM AUTUMNALE
COLECALCIFEROL+ALENDRONIC ACID
GLUCOSAMINE SULFATE
HYALURONIC ACID
HYDROXYCHLOROQUINE SULFATE
IBUPROFEN LYSINATE
INDOMETACIN
KETOPROFEN
MEFENAMIC ACID
MELOXICAM
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
201
17 (17%)
4 (4%)
5 (5%)
2 (2%)
2 (2%)
1 (<1%)
0
2 (2%)
0
1 (<1%)
18
4
6
1
2
1
0
1
1
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
2
0
0
0
0
0
0
0
0
(18%)
(4%)
(6%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(2%)
19
11
1
3
1
2
1
1
1
0
0
0
0
0
0
0
0
0
0
0
(19%)
(11%)
(<1%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
22 (22%)
6 (6%)
4 (4%)
0
1 (1%)
0
4 (4%)
2 (2%)
0
0
1
0
0
0
1
1
1
1
1
1
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
13
4
3
1
2
1
1
0
1
0
(13%)
(4%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
17
3
4
3
1
2
1
1
0
1
(17%)
(3%)
(4%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
DERMATOLOGICALS
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
BENADRYL (NOS)
BECLOMETASONE DIPROPIONATE
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
HYDROCORTISONE
ETHINYLOESTRADIOL+CYPROTERONE
ACETATE
TOCOPHEROL
TRIAMCINOLONE
ACYCLOVIR
BETAMETHASONE DIPROPIONATE
BETAMETHASONE+CALCIPOTRIOL
BUTOCONAZOLE NITRATE
CLINDAMYCIN PHOSPHATE+TRETINOIN
CLINDAMYCIN+BENZOYL PEROXIDE
DESOXIMETASONE
DEXAMETHASONE
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
PIROXICAM
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
QUININE
0
0
0
0
0
1 (<1%)
RISEDRONATE SODIUM
0
0
0
0
1 (<1%)
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
7
4
0
0
1
0
0
0
1
1
1
0
0
0
1
0
(7%)
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
8 (8%)
6 (6%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
5 (5%)
2 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
9
3
1
0
0
1
0
1
0
0
0
1
0
0
0
1
(9%)
(3%)
(1%)
(1%)
(1%)
(1%)
(1%)
8 (8%)
6 (6%)
0
0
0
0
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
9 (9%)
8 (8%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
CONFIDENTIAL
202
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
FLUCONAZOLE
0
0
0
1 (1%)
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0
TOCOPHERYL
0
0
0
0
0
1 (<1%)
ACETATE+ALLANTOIN+HYALURONATE
SODIUM+TELMESTEINE+VITIS
VINIFERA+PIROCTONE
OLAMINE+BISABOLOL
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PHENPROCOUMON
0
0
0
1 (1%)
0
0
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
9
3
1
1
1
1
2
0
0
0
0
0
0
(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
SENSORY ORGANS
Any medication
DICLOFENAC
TRIAMCINOLONE ACETONIDE
DICLOFENAC SODIUM
HYDROCORTISONE
CIPROFLOXACIN
EPINEPHRINE
KETOROLAC TROMETAMOL
OLOPATADINE HYDROCHLORIDE
PROCAINE HYDROCHLORIDE
TRIAMCINOLONE
XYLOMETAZOLINE HYDROCHLORIDE
7 (7%)
1 (<1%)
2 (2%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
12
1
1
1
1
1
0
0
1
1
2
1
(12%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
10
4
2
1
2
1
0
0
0
1
1
0
1
(10%)
(4%)
(2%)
(<1%)
(2%)
(<1%)
8
1
1
1
1
0
1
1
1
1
0
0
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
8
5
0
2
0
0
0
0
1
0
0
0
0
(8%)
(5%)
6
2
2
0
0
0
0
1
0
0
0
1
(6%)
(2%)
(2%)
(2%)
(1%)
(1%)
(1%)
3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
7 (7%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
3 (3%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
4 (4%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
9 (9%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
CONFIDENTIAL
203
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
204
4 (4%)
3 (3%)
0
0
0
1 (<1%)
0
0
0
0
0
0
2 (2%)
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3 (3%)
1 (<1%)
0
0
4 (4%)
2 (2%)
1 (<1%)
0
2
2
0
0
(2%)
(2%)
4
0
0
0
0
0
1
0
1
0
1
1
(4%)
2
0
1
1
(2%)
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
2 (2%)
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0
4 (4%)
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
2
0
0
2
3 (3%)
2 (2%)
1 (<1%)
0
(2%)
(2%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACYCLOVIR
0
0
0
0
0
1 (<1%)
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DEXAMETHASONE+CIPROFLOXACIN
0
0
0
0
1 (<1%)
0
HEPARIN SODIUM
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
TETRYZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
3 (3%)
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
1 (<1%)
1 (<1%)
0
0
3
1
0
0
1
1
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(3%)
(1%)
(1%)
(1%)
(1%)
(1%)
2 (2%)
0
1 (<1%)
0
0
0
3 (3%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
0
0
0
0
Note: A medication may be included in more than one ATC Level category and appear more than once.
YM2008/00019/00
B2C109575
4 (4%)
0
1 (<1%)
0
0
0
CONFIDENTIAL
205
VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM
ALOE
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
ATROPA BELLADONNA+MERCURIC
CHLORIDE+EUPHRASIA OFFICINALIS
CHONDROITIN SULFATE SODIUM
CINNAMOMUM VERUM
DOCOSAHEXANOIC
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
GLUCOSE
IOVERSOL
LINUM USITATISSIMUM
MEDICATION UNKNOWN
POTASSIUM IODIDE
VITIS VINIFERA
Protocol: B2C109575
Population: Intent-to-Treat
Page 20 of 20
Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
0
0
0
0
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
QUININE
0
0
0
0
0
1 (<1%)
CONFIDENTIAL
206
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
68 (67%)
58 (57%)
51 (50%)
67 (67%)
58 (57%)
54 (53%)
(27%)
(8%)
(4%)
(2%)
(2%)
(3%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
22
5
4
2
2
0
1
1
0
1
0
1
0
1
1
2
1
0
1
0
0
1
0
1
1
0
0
0
0
(22%)
(5%)
(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
20
5
2
1
3
2
0
2
0
1
0
2
1
1
0
0
3
0
1
1
0
1
0
0
0
0
0
1
0
(20%)
(5%)
(2%)
(<1%)
(3%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
30 (30%)
7 (7%)
3 (3%)
1 (1%)
2 (2%)
1 (1%)
3 (3%)
0
1 (1%)
1 (1%)
0
2 (2%)
4 (4%)
2 (2%)
1 (1%)
0
0
0
0
0
0
0
1 (1%)
0
0
1 (1%)
0
0
1 (1%)
27
5
6
2
0
2
1
1
4
2
2
1
1
0
1
1
0
0
1
0
0
0
0
0
0
0
1
0
1
(27%)
(5%)
(6%)
(2%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
26
3
7
1
0
1
1
2
1
2
1
1
1
1
2
1
1
1
0
0
1
0
1
1
1
1
0
0
0
(25%)
(3%)
(7%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
28
8
4
2
2
3
2
1
1
0
4
0
0
2
0
1
0
2
0
1
1
0
0
0
0
0
1
1
0
CONFIDENTIAL
207
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
208
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TRIAMCINOLONE
0
2 (2%)
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BISMUTH SUBSALICYLATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CIMETIDINE
1 (<1%)
0
0
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
HYOSCINE BUTYLBROMIDE
0
0
1 (<1%)
0
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
PHLOROGLUCINOL+TRIMETHYLPHLOROGLU
1 (<1%)
0
0
0
0
0
CINOL
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
29
5
5
2
2
1
1
2
0
2
1
0
(28%)
(5%)
(5%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(2%)
(2%)
(<1%)
27
4
6
2
2
1
1
1
0
1
3
1
(27%)
(4%)
(6%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(3%)
(<1%)
21
11
1
3
1
2
2
2
1
1
1
1
(2%)
(21%)
(11%)
(<1%)
(3%)
(<1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
29 (29%)
6 (6%)
4 (4%)
6 (6%)
1 (1%)
0
0
1 (1%)
4 (4%)
2 (2%)
1 (1%)
2 (2%)
0
18
4
3
0
2
1
1
0
1
0
0
1
(18%)
(4%)
(3%)
(<1%)
26
3
4
2
1
3
2
1
1
1
0
1
1 (<1%)
(2%)
(<1%)
(<1%)
(<1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
(25%)
(3%)
(4%)
(2%)
(<1%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
RESPIRATORY SYSTEM
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
LORATADINE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
BUDESONIDE
PHENIRAMINE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
FLUTICASONE FUROATE
PSEUDOEPHEDRINE
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
AZELASTINE HYDROCHLORIDE
CONFIDENTIAL
209
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM
0
0
1 (<1%)
0
0
0
BICARBONATE+THIAMINE+CALCIUM
CARBONATE+AMYLASE+SCOPOLIA
CARNIOLICA+SYZYGIUM
AROMATICUM+FOENICULUM VULGARE OIL
THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
210
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FEXOFENADINE HYDROCHLORIDE
2 (2%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
PSEUDOEPHEDRINE HYDROCHLORIDE
0
0
2 (2%)
0
0
3 (3%)
BROMHEXINE
1 (<1%)
0
1 (<1%)
1 (1%)
0
1 (<1%)
CETIRIZINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
COUGH COLD PREPARATIONS NOS
0
2 (2%)
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
CHLORPHENAMINE MALEATE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
DESLORATADINE
2 (2%)
0
0
0
1 (<1%)
0
CHLORPHENAMINE
0
1 (<1%)
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
GUAIFENESIN
0
0
1 (<1%)
0
0
1 (<1%)
GUAIFENESIN+PSEUDOEPHEDRINE
0
1 (<1%)
0
0
0
1 (<1%)
HYDROCHLORIDE
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
0
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
1 (<1%)
0
0
0
0
SULFATE+LORATADINE
PSEUDOEPHEDRINE
0
0
0
0
0
2 (2%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL SINUS (NOS)
0
0
0
1 (1%)
0
1 (<1%)
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CETIRIZINE
0
0
0
0
1 (<1%)
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
26 (25%)
9 (9%)
9 (9%)
4 (4%)
22 (22%)
9 (9%)
7 (7%)
4 (4%)
19 (19%)
9 (9%)
8 (8%)
2 (2%)
26 (26%)
6 (6%)
6 (6%)
3 (3%)
23 (23%)
11 (11%)
4 (4%)
6 (6%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
21 (21%)
8 (8%)
2 (2%)
7 (7%)
YM2008/00019/00
B2C109575
NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID
CONFIDENTIAL
211
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------EBASTINE
1 (<1%)
0
0
0
0
0
FLUNISOLIDE
0
0
0
0
1 (<1%)
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN+DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
GUAIFENESIN+HYDROCODONE
0
0
1 (<1%)
0
0
0
BITARTRATE
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
MONTELUKAST SODIUM
1 (<1%)
0
0
0
0
0
PARACETAMOL+CHLORPHENAMINE+PHENYL
0
0
0
0
1 (<1%)
0
EPHRINE HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE
SUCCINATE
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
XYLOMETAZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
212
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACETYLSALICYLIC
0
1 (<1%)
0
3 (3%)
0
0
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
0
1 (<1%)
1 (<1%)
1 (1%)
1 (<1%)
0
CLONAZEPAM
2 (2%)
0
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
ESCITALOPRAM OXALATE
1 (<1%)
1 (<1%)
0
2 (2%)
0
0
FLUOXETINE HYDROCHLORIDE
1 (<1%)
0
0
3 (3%)
0
0
SERTRALINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
BUPROPION HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
CITALOPRAM HYDROBROMIDE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
EXCEDRIN (NOS)
0
0
0
0
0
3 (3%)
HYDROXYZINE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
METAMIZOLE SODIUM
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
SUMATRIPTAN
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
0
1 (<1%)
0
0
0
1 (<1%)
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
CAFFEINE
1 (<1%)
0
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
23 (23%)
21 (21%)
21 (21%)
19 (19%)
20 (20%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
15 (15%)
YM2008/00019/00
B2C109575
CARDIOVASCULAR SYSTEM
Any medication
CONFIDENTIAL
213
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL
ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+CAFFEINE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
PARACETAMOL+CAFFEINE+BUTALBITAL
0
0
0
0
1 (<1%)
0
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
214
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ENALAPRIL
2 (2%)
0
2 (2%)
3 (3%)
3 (3%)
1 (<1%)
HYDROCHLOROTHIAZIDE
2 (2%)
4 (4%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
AMLODIPINE BESILATE
1 (<1%)
2 (2%)
1 (<1%)
3 (3%)
1 (<1%)
2 (2%)
SIMVASTATIN
1 (<1%)
2 (2%)
0
0
2 (2%)
2 (2%)
VERAPAMIL
3 (3%)
1 (<1%)
0
1 (1%)
2 (2%)
0
AMLODIPINE
1 (<1%)
1 (<1%)
0
0
4 (4%)
0
VERAPAMIL HYDROCHLORIDE
1 (<1%)
0
1 (<1%)
3 (3%)
1 (<1%)
0
ENALAPRIL MALEATE
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
LISINOPRIL
0
0
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
PERINDOPRIL
0
1 (<1%)
0
0
4 (4%)
0
ATORVASTATIN CALCIUM
1 (<1%)
0
0
1 (1%)
0
2 (2%)
HYDROCHLOROTHIAZIDE+LOSARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
POTASSIUM
INDAPAMIDE
0
0
1 (<1%)
1 (1%)
0
2 (2%)
IRBESARTAN
0
2 (2%)
1 (<1%)
1 (1%)
0
0
LOSARTAN POTASSIUM
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
VALSARTAN
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
FISH OIL
0
0
2 (2%)
0
0
1 (<1%)
FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
215
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CAPTOPRIL
1 (<1%)
0
0
0
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LOVASTATIN
0
0
0
0
1 (<1%)
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0
TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
24 (24%)
14 (14%)
14 (14%)
17 (17%)
14 (14%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
14 (14%)
YM2008/00019/00
B2C109575
CONFIDENTIAL
216
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
Any medication
17 (17%)
18 (18%)
20 (20%)
22 (22%)
13 (13%)
16 (16%)
FLUTICASONE PROPIONATE
5 (5%)
4 (4%)
11 (11%)
6 (6%)
4 (4%)
3 (3%)
MOMETASONE FUROATE
5 (5%)
6 (6%)
1 (<1%)
4 (4%)
3 (3%)
4 (4%)
BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
BENADRYL (NOS)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
3 (3%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACYCLOVIR
0
0
1 (<1%)
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BETAMETHASONE+CALCIPOTRIOL
0
0
0
1 (1%)
0
0
CLINDAMYCIN PHOSPHATE+TRETINOIN
0
0
0
1 (1%)
0
0
CLINDAMYCIN+BENZOYL PEROXIDE
0
0
0
1 (1%)
0
0
DESOXIMETASONE
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
CONFIDENTIAL
217
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------IBUPROFEN
9 (9%)
7 (7%)
8 (8%)
6 (6%)
4 (4%)
2 (2%)
ETHINYLOESTRADIOL+LEVONORGESTREL
3 (3%)
2 (2%)
1 (<1%)
0
1 (<1%)
4 (4%)
ETHINYLOESTRADIOL+DROSPIRENONE
3 (3%)
0
1 (<1%)
2 (2%)
2 (2%)
1 (<1%)
ETHINYLOESTRADIOL+NORGESTIMATE
4 (4%)
0
0
0
0
2 (2%)
NAPROXEN SODIUM
1 (<1%)
1 (<1%)
0
2 (2%)
1 (<1%)
0
ESTRADIOL
0
1 (<1%)
0
1 (1%)
0
1 (<1%)
ESTROGENS CONJUGATED
0
0
0
1 (1%)
2 (2%)
0
ETHINYLOESTRADIOL+DESOGESTREL
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
ETHINYLOESTRADIOL+NORETHISTERONE
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
ACETATE
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
NAPROXEN
0
2 (2%)
1 (<1%)
0
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
ETHINYLOESTRADIOL+GESTODENE
0
0
0
0
2 (2%)
0
ETHINYLOESTRADIOL+NORETHISTERONE
0
0
2 (2%)
0
0
0
CYPROTERONE ACETATE
0
1 (<1%)
0
0
0
0
DESOGESTREL
0
0
0
1 (1%)
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
ESTRADIOL+DYDROGESTERONE
0
1 (<1%)
0
0
0
0
ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
218
17
9
4
0
1
2
1
0
0
0
0
0
0
0
0
1
0
0
1
0
(17%)
(9%)
(4%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
16
7
4
1
1
1
1
2
0
1
0
0
0
0
1
0
0
0
0
1
(16%)
(7%)
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
14
8
2
1
0
0
1
1
0
1
1
1
0
0
0
0
0
1
0
0
(14%)
(8%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
15 (15%)
6 (6%)
3 (3%)
2 (2%)
2 (2%)
0
0
0
0
0
0
1 (1%)
1 (1%)
1 (1%)
0
0
0
0
0
0
14
4
6
0
1
0
0
0
1
0
1
0
0
0
0
0
1
0
0
0
(14%)
(4%)
(6%)
(<1%)
(<1%)
(<1%)
(<1%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
11
2
7
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
(11%)
(2%)
(7%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
DICLOFENAC
NAPROXEN SODIUM
ALENDRONATE SODIUM
DICLOFENAC SODIUM
NAPROXEN
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE
KETOPROFEN
KETOROLAC TROMETAMOL
CELECOXIB
CHONDROITIN SULFATE SODIUM
COLCHICUM AUTUMNALE
COLECALCIFEROL+ALENDRONIC ACID
CYCLOBENZAPRINE HYDROCHLORIDE
HYALURONIC ACID
HYDROXYCHLOROQUINE SULFATE
INDOMETACIN
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
LEVONORGESTREL
0
0
1 (<1%)
0
0
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0
TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
219
9 (9%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
9
3
1
1
1
1
2
0
0
0
0
0
0
6 (6%)
4 (4%)
0
0
1 (<1%)
5 (5%)
4 (4%)
1 (<1%)
1 (<1%)
0
(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
10
4
2
1
2
1
0
0
0
1
1
0
1
(10%)
(4%)
(2%)
(<1%)
(2%)
(<1%)
(8%)
(5%)
(<1%)
8
5
0
2
0
0
0
0
1
0
0
0
0
5 (5%)
2 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
8
3
1
0
0
(8%)
(3%)
(1%)
(<1%)
(<1%)
(2%)
(1%)
3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
7 (7%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
8
6
0
0
0
8
7
0
0
0
(8%)
(6%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
(8%)
(7%)
YM2008/00019/00
B2C109575
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------MELOXICAM
0
0
0
0
1 (<1%)
0
METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
PIROXICAM
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
RISEDRONATE SODIUM
0
0
0
0
1 (<1%)
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FERROUS SULPHATE
0
0
0
1 (1%)
0
1 (<1%)
CALCIUM CHLORIDE
0
0
0
0
1 (<1%)
0
CLOPIDOGREL BISULFATE
0
0
0
1 (1%)
0
0
FERROUS GLYCINE SULFATE
1 (<1%)
0
0
0
0
0
IRON
0
0
0
0
1 (<1%)
0
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
PHENPROCOUMON
0
0
0
1 (1%)
0
0
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
(6%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(3%)
9
1
1
1
1
0
0
1
2
0
0
0
0
0
1
0
0
1
(9%)
(<1%)
(<1%)
(<1%)
(<1%)
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
8
1
1
1
1
1
1
1
0
1
0
0
0
1
0
1
0
0
(4%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
5
2
2
0
0
0
1
0
0
0
0
1
0
0
0
0
0
0
(5%)
(2%)
(2%)
(2%)
(1%)
(1%)
2 (2%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(2%)
Note: A medication may be included in more than one ATC Level category and appear more than once.
(3%)
YM2008/00019/00
B2C109575
6
2
0
1
0
1
0
0
0
0
1
0
0
0
0
0
1
0
CONFIDENTIAL
220
SENSORY ORGANS
Any medication
TRIAMCINOLONE ACETONIDE
DICLOFENAC
DICLOFENAC SODIUM
HYDROCORTISONE
EPINEPHRINE
KETOROLAC TROMETAMOL
OLOPATADINE HYDROCHLORIDE
TRIAMCINOLONE
ACYCLOVIR
CLONIDINE HYDROCHLORIDE
DEXAMETHASONE
DEXAMETHASONE+CIPROFLOXACIN
HYALURONIC ACID
INDOMETACIN
PIROXICAM
POTASSIUM IODIDE
XYLOMETAZOLINE HYDROCHLORIDE
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------IMMUNOTHERAPY{NOS}
1 (<1%)
2 (2%)
2 (2%)
0
0
2 (2%)
ESTRADIOL
0
1 (<1%)
0
1 (1%)
0
1 (<1%)
ESTROGENS CONJUGATED
0
0
0
1 (1%)
2 (2%)
0
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
2 (2%)
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
1 (<1%)
1 (<1%)
0
0
3
1
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(3%)
(1%)
(1%)
(1%)
(1%)
(1%)
2 (2%)
0
1 (<1%)
0
0
0
3 (3%)
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
YM2008/00019/00
B2C109575
3 (3%)
0
1 (<1%)
0
0
0
CONFIDENTIAL
221
VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM
ALOE
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
CHONDROITIN SULFATE SODIUM
CINNAMOMUM VERUM
DOCOSAHEXANOIC
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
IOVERSOL
LINUM USITATISSIMUM
MEDICATION UNKNOWN
POTASSIUM IODIDE
VITIS VINIFERA
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 16
Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment
222
ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
Note: A medication may be included in more than one ATC Level category and appear more than once.
0
0
CONFIDENTIAL
ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
2 (2%)
1 (<1%)
3 (3%)
2 (2%)
2 (2%)
1 (<1%)
AMOXICILLIN
1 (<1%)
0
1 (<1%)
0
0
0
TRIHYDRATE+CLAVULANATE POTASSIUM
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ACYCLOVIR
0
0
1 (<1%)
0
0
0
AMOXICILLIN TRIHYDRATE
0
0
0
0
1 (<1%)
0
AZITHROMYCIN
0
1 (<1%)
0
0
0
0
LEVOFLOXACIN
0
0
0
0
0
1 (<1%)
PHENOXYMETHYLPENICILLIN POTASSIUM
1 (<1%)
0
0
0
0
0
RIFAMPICIN
0
0
0
1 (1%)
0
0
SULFAMETHOXAZOLE+TRIMETHOPRIM
0
0
0
1 (1%)
0
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 6.21
Summary of Screening Lung Function Test Results
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Screening
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Pre-bronchodilator
n
102
101
101
100
101
102
FEV1 (L)
Mean
2.211
2.257
2.243
2.255
2.127
2.165
SD
0.6740
0.8031
0.6494
0.6315
0.6067
0.6143
Median
2.209
2.148
2.223
2.172
2.079
2.113
Min.
0.83
1.04
1.06
1.03
0.83
0.86
Max.
4.48
4.54
3.63
4.02
3.76
4.37
102
66.9
11.97
68.1
41
90
101
65.8
13.48
66.2
40
90
101
66.5
10.75
66.6
42
88
100
67.6
11.79
67.8
41
90
101
65.3
12.08
66.0
42
89
102
65.9
12.29
66.5
40
89
Post-bronchodilator
FEV1 (L)
n
Mean
SD
Median
Min.
Max.
102
2.767
0.8004
2.676
1.18
5.26
101
2.775
0.9468
2.654
1.26
5.17
101
2.806
0.7814
2.789
1.45
4.59
100
2.792
0.7369
2.693
1.32
4.81
101
2.668
0.7027
2.555
1.32
4.23
102
2.702
0.7095
2.675
1.07
5.05
Percent Reversibility
FEV1 (%)
n
Mean
SD
Median
Min.
Max.
102
26.6
15.37
21.2
7
86
101
24.2
13.45
20.4
2
76
101
26.3
15.39
22.4
6
100
100
25.2
16.20
20.1
12
125
101
27.4
20.74
20.0
12
123
102
26.4
15.45
22.1
-12
102
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
223
Percent Predicted
FEV1 (%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 6.21
Summary of Screening Lung Function Test Results
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Screening
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Absolute Reversibility n
102
101
101
100
101
102
FEV1 (mL)
Mean
555.5
517.8
562.7
537.0
540.2
537.0
SD
300.26
271.20
291.05
280.18
339.07
253.50
Median
442.0
432.0
513.0
464.0
452.0
477.5
Min.
164
29
148
201
200
-229
Max.
1697
1317
1564
1501
2207
1427
CONFIDENTIAL
224
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.22
Summary of Treatment Compliance (%)
101
0
75 (74%)
26 (26%)
101
0
82 (81%)
19 (19%)
100
0
79 (79%)
21 (21%)
100
3 (3%)
79 (79%)
18 (18%)
101
0
77 (76%)
24 (24%)
225
CONFIDENTIAL
n
<80%
>=80% to =<100%
>100%
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.23
Summary of Percent Predicted FEV1 Strata: As Randomised and Actual
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------------------------------As Randomised Stratum
Stratum 1: >=40% - <=65%
44 (43%)
44 (44%)
44 (44%)
44 (44%)
45 (45%)
44 (43%)
265 (44%)
Stratum 2: >65% - <=90%
58 (57%)
57 (56%)
57 (56%)
56 (56%)
56 (55%)
58 (57%)
342 (56%)
Actual Stratum
Stratum 1: >=40% - <=65%
Stratum 2: >65% - <=90%
44 (43%)
58 (57%)
46 (46%)
55 (54%)
43 (43%)
58 (57%)
42 (42%)
58 (58%)
47 (47%)
54 (53%)
46 (45%)
56 (55%)
268 (44%)
339 (56%)
CONFIDENTIAL
226
YM2008/00019/00
B2C109575
Note: Actual stratum is determined using Day 1 Pre-dose Percent Predicted FEV1.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.24
Summary of Percent Predicted FEV1 (%) Day 1 Pre-Dose by Actual Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------Stratum 1: >=40% - <=65% n
44
46
43
42
47
46
268
Mean
55.9
54.2
57.8
56.2
55.2
56.1
55.9
SD
6.70
7.78
5.20
7.04
7.15
6.29
6.78
Median 56.6
54.4
59.1
58.9
56.7
57.1
57.1
Min.
41
34
45
40
40
42
34
Max.
65
64
65
65
65
65
65
Stratum 2: >65% - <=90%
58
75.8
6.96
74.5
65
90
55
77.1
6.97
77.3
66
90
58
76.8
7.01
76.2
66
90
58
78.3
7.13
78.5
66
90
54
75.5
7.64
74.9
65
91
339
76.6
7.05
76.6
65
91
YM2008/00019/00
B2C109575
Note: Actual stratum is determined using Day 1 Pre-dose Percent Predicted FEV1.
56
76.0
6.50
76.8
65
87
CONFIDENTIAL
227
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.103
Summary of Background Steroid Dose During Treatment
CONFIDENTIAL
228
YM2008/00019/00
B2C109575
CONFIDENTIAL
YM2008/00019/00
B2C109575
229
234
235
236
237
238
239
240
241
242
243
244
245
246
248
250
252
254
256
257
258
259
CONFIDENTIAL
YM2008/00019/00
B2C109575
230
260
261
262
263
264
265
266
268
269
270
271
272
273
274
275
276
277
278
279
280
284
290
CONFIDENTIAL
YM2008/00019/00
B2C109575
Table 7.12 Slope Estimate of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) at Day 28 by %Predicted FEV1 Stratum (Intent-to-Treat Population) . .
Table 7.13 Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 by %Predicted FEV1 Stratum (Intent-to-Treat Population) . .
Table 7.14 Summary of Raw Serial FEV1 (L) (Intent-to-Treat Population) . . . . . . . .
Table 7.15 Summary of Absolute Change from Baseline in Serial FEV1 (L)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.16 Summary of Percentage Change from Baseline in Serial FEV1 (%%)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.17 Repeated Measures Analysis of Serial FEV1 (L) Day 1 (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.18 Repeated Measures Analysis of Serial FEV1 (L) Day 28
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.19 Summary of Weighted Mean Change from Baseline in 24 hour Serial
Clinic FEV1 (L) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.20 Statistical Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) All Subjects, including 6-12 hour time points
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.21 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) All Subjects excluding 6-12 hour time points
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.22 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Subset of Subjects who had the 6-12 hour time
points measured. All time points included (Intent-to-Treat Population) . . . . . . . .
Table 7.23 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Subset of Subjects who had 6-12 hour time points
measured, excluding 6-12 hour time points (Intent-to-Treat Population) . . . . . .
Table 7.24 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Observations without rescue medication
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.25 Summary of Post-salbutamol/albuterol FEV1 (L) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.26 Summary of Post-salbutamol/albuterol FEV1 (L) Differences
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.27 Statistical Analysis of difference in post-salbutamol/albuterol FEV1 (L)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.28 Summary of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.29 Statistical Analysis of Maximum Increase from Baseline in FEV1 (L)
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.30 Summary of Weighted Mean Change from Baseline in FEV1 (L)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
231
292
293
294
300
303
306
319
333
334
335
336
337
338
339
340
341
342
343
344
CONFIDENTIAL
YM2008/00019/00
B2C109575
Table 7.31 Statistical Analysis of Weighted Mean Change from Baseline in FEV1
(L) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.32 Summary of the Proportion of Subjects Obtaining >= 200mL and >=
12% Increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . .
Table 7.33 Summary of the Cumulative Proportion of Subjects Obtaining >=200mL
and >=12% increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.34 Summary of the Proportion of Subjects Obtaining >= 15% Increase
from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 7.35 Summary of the Cumulative Proportion of Subjects Obtaining >=15%
increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . . . . . . .
Table 7.36 Summary of Peak Post-Dose FEV1 (L) (0-4hrs) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.37 Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.38 Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.39 Change from Baseline in PM PEF (L/min) (Intent-to-Treat Population) . .
Table 7.40 Statistical Analysis of Change from Baseline in PM PEF (L/min)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.41 Change from Baseline in AM PEF (L/min) (Intent-to-Treat Population) . .
Table 7.42 Statistical Analysis of Change from Baseline in AM PEF (L/min)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.43 Change from Baseline in Percentage of Symptom Free 24 Hour
Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.44 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free 24 Hour Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 7.45 Change from Baseline in Percentage of Rescue Free 24 Hour Periods
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.46 Statistical Analysis of Change from Baseline in Percentage of Rescue
Free 24 Hour Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.47 Change from Baseline in Percentage of Symptom Free Days
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.48 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free Days (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.49 Change from Baseline in Percentage of Symptom Free Nights
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.50 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free Nights (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.51 Change from Baseline in Percentage of Rescue Free Days
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
232
345
346
347
348
349
350
351
352
353
362
363
372
373
374
375
376
377
378
379
380
381
CONFIDENTIAL
YM2008/00019/00
B2C109575
233
382
383
384
385
386
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.1
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
50mcg
CONFIDENTIAL
234
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
0.3
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
0.4
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.2
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
0.4
CONFIDENTIAL
235
0.3
0.2
0.1
12.5mcg
25mcg
Treatment
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.
Regression line is based on the adjusted means of the Placebo and treatment groups.
50mcg
YM2008/00019/00
B2C109575
0.0
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.3
Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
236
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.4
Empirical Distribution Function for Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
1.0
CONFIDENTIAL
237
Cumulative Probability
0.8
0.6
0.4
0.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Figure 7.5
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol
50mcg
CONFIDENTIAL
238
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
0.3
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
0.4
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Figure 7.6
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol
0.4
CONFIDENTIAL
239
0.3
0.2
0.1
12.5mcg
25mcg
Treatment
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.
Regression line is based on the adjusted means of the Placebo and treatment groups.
50mcg
YM2008/00019/00
B2C109575
0.0
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Figure 7.7
Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol
This section contained data from each individual patient, rather than in aggregate. They have been excluded to
protect patient privacy. Anonymized data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
240
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Figure 7.8
Empirical Distribution Function for Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per-Protocol
1.0
CONFIDENTIAL
241
Cumulative Probability
0.8
0.6
0.4
0.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.9
Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)
0.35
0.30
0.20
0.25
0.15
14
28
29
0.10
CONFIDENTIAL
242
0.40
0.05
0.0
Day of Study
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, visit, visit by treatment interaction
and visit by baseline interaction
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.10
Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L) - Differences from Placebo
0.25
0.15
0.10
0.05
0.0
CONFIDENTIAL
243
0.20
-0.05
-0.10
14
28
Day of Study
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, visit, visit by treatment interaction
and visit by baseline interaction
29
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.11
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum
0.4
0.2
CONFIDENTIAL
244
0.3
0.1
0.0
-0.1
3mcg
6.25mcg
Stratum
12.5mcg
>=40% - <=65%
25mcg
50mcg
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum, treatment
and treatment by stratum interaction
YM2008/00019/00
B2C109575
-0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.12
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum
0.3
CONFIDENTIAL
245
0.4
0.2
0.1
12.5mcg
25mcg
50mcg
Treatment
Stratum
>=40% - <=65%
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum, treatment,
and treatment by stratum interaction.
YM2008/00019/00
B2C109575
0.0
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.13
Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
DAY=1
50mcg
CONFIDENTIAL
246
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
0.3
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
0.4
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.13
Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
DAY=28
50mcg
CONFIDENTIAL
247
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
0.3
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
0.4
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.14
Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean 24 hour Serial FEV1 (L)
Day=1
0.4
0.2
CONFIDENTIAL
248
0.3
0.1
0.0
-0.1
Analysis 1
3mcg
Analysis 2
6.25mcg
Analysis 3
12.5mcg
Analysis 4
25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
Analysis 1: All Subjects. The 6-12 hr time points are included.
Analysis 2: All Subjects. The 6-12 hr time points are excluded.
Analysis 3: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are included.
Analysis 4: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are excluded.
YM2008/00019/00
B2C109575
-0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.14
Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean 24 hour Serial FEV1 (L)
Day=28
0.4
0.2
CONFIDENTIAL
249
0.3
0.1
0.0
-0.1
Analysis 1
3mcg
Analysis 2
6.25mcg
Analysis 3
12.5mcg
Analysis 4
25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
Analysis 1: All Subjects. The 6-12 hr time points are included.
Analysis 2: All Subjects. The 6-12 hr time points are excluded.
Analysis 3: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are included.
Analysis 4: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are excluded.
YM2008/00019/00
B2C109575
-0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.15
Plot of Mean Clinic FEV1 (L) Over Time
Day 1
3.0
2.6
2.4
2.2
CONFIDENTIAL
250
2.8
2.0
2
10
12
14
16
18
20
22
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 12hrs,
16hrs, 20hrs, 22hrs, 23hrs, 24hrs
24
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.15
Plot of Mean Clinic FEV1 (L) Over Time
Day 28
3.0
2.6
2.4
20
22
2.2
CONFIDENTIAL
251
2.8
2.0
6
10
12
14
16
18
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 12hrs,
16hrs, 20hrs, 22hrs, 23hrs, 24hrs
24
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.16
Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 1
0.4
0.3
0.2
0.1
CONFIDENTIAL
252
0.5
0.0
1
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.16
Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 28
0.4
0.3
0.2
CONFIDENTIAL
253
0.5
0.1
0.0
3
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.17
Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 1
20
15
10
CONFIDENTIAL
254
25
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.17
Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 28
20
10
15
CONFIDENTIAL
255
25
0
1
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.18
Repeated Measures Adjusted Mean Change from Baseline in FEV1 (L) Over Time
Day 1
0.4
0.3
0.2
0.1
CONFIDENTIAL
256
0.5
0.0
2
10
12
14
16
18
20
22
24
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.19
Repeated Measures Adjusted Mean Change from Baseline in FEV1 (L) Over Time
Day 28
0.4
0.3
0.2
0.1
CONFIDENTIAL
257
0.5
0.0
2
10
12
14
16
18
20
22
24
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.20
Repeated Measures Adjusted Treatment Differences from Placebo in Change from Baseline FEV1 (L)
Over Time - Day 1
0.3
0.2
0.1
0.0
CONFIDENTIAL
258
0.4
-0.1
2
10
12
14
16
18
20
22
24
Time (hours)
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.21
Repeated Measures Adjusted Treatment Differences from Placebo in Change from Baseline FEV1 (L)
Over Time - Day 28
0.3
0.2
0.1
20
22
0.0
CONFIDENTIAL
259
0.4
-0.1
2
10
12
14
16
18
24
Time (hours)
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.22
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 - Day 1
50mcg
CONFIDENTIAL
260
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age,
stratum and treatment
0.2
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.23
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 1 - Screening
50mcg
CONFIDENTIAL
261
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age,
stratum and treatment
0.2
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.24
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 - Screening
50mcg
CONFIDENTIAL
262
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.25
Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4hrs)
Day 28
50mcg
CONFIDENTIAL
263
Treatment
25mcg
12.5mcg
6.25mcg
-0.2
-0.1
0.0
0.1
0.2
0.3
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
0.4
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.26
Mean Change from Baseline in PM PEF (L/min)
60
40
30
10
20
CONFIDENTIAL
264
50
-10
7
14
21
Day
Placebo
3mcg
Treatment
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.27
Mean Change from Baseline in AM PEF (L/min)
60
40
30
10
20
CONFIDENTIAL
265
50
-10
7
14
21
Day
Placebo
3mcg
Treatment
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.109
Proportion of Subjects Obtaining >= 200mL and >= 12% Increase from Baseline FEV1 (L)
Day 1
70
50
40
30
20
10
12
14
16
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
18
20
22
24
YM2008/00019/00
B2C109575
CONFIDENTIAL
266
Percentage of Subjects
60
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Figure 7.109
Proportion of Subjects Obtaining >= 200mL and >= 12% Increase from Baseline FEV1 (L)
Day 28
70
50
30
40
CONFIDENTIAL
267
Percentage of Subjects
60
20
10
12
14
16
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
18
20
22
24
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.111
Adjusted Treatment Differences of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
50mcg
CONFIDENTIAL
268
Treatment
25mcg
12.5mcg
6.25mcg
-5
10
15
20
25
30
35
40
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.112
Adjusted Treatment Differences of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
50mcg
CONFIDENTIAL
269
Treatment
25mcg
12.5mcg
6.25mcg
-5
10
15
20
25
30
35
40
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.113
Adjusted Treatment Differences of Change from Baseline in PM PEF (L/min), Days 1-28
50mcg
CONFIDENTIAL
270
Treatment
25mcg
12.5mcg
6.25mcg
10
20
30
40
50
60
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.114
Adjusted Treatment Differences of Change from Baseline in AM PEF (L/min), Days 1-28
50mcg
CONFIDENTIAL
271
Treatment
25mcg
12.5mcg
6.25mcg
10
20
30
40
50
60
YM2008/00019/00
B2C109575
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.1
Summary of Trough FEV1 (L) (LOCF)
Intent-to-Treat
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Trough FEV1 (L)
n
95
98
99
97
99
100
Mean
2.340
2.489
2.540
2.571
2.432
2.503
SD
0.7796
0.9238
0.7789
0.7867
0.7016
0.6678
Median
2.276
2.368
2.442
2.419
2.340
2.430
Min.
1.03
0.66
1.07
1.13
1.07
1.20
Max.
4.53
5.02
4.50
4.84
4.03
4.98
272
95
98
99
97
99
Mean
SD
Median
Min.
Max.
0.163
0.4100
0.066
-0.77
1.79
0.197
0.3994
0.119
-0.70
1.45
0.217
0.3693
0.183
-0.91
1.80
0.268
0.3871
0.201
-0.52
1.71
0.282
0.3295
0.278
-0.77
1.32
100
0.305
0.3106
0.248
-0.23
1.23
CONFIDENTIAL
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.2
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF)
Intent-to-Treat
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.003
Estimate of Slope
95% C.I.
2.545 mL/mcg
(0.893, 4.196)
CONFIDENTIAL
273
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.3
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF) Excluding Placebo
Intent-to-Treat
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.037
Estimate of Slope
95% C.I.
1.924 mL/mcg
(0.120, 3.728)
CONFIDENTIAL
274
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups (Placebo is not included).
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.4
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Intent-to-Treat
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.388
2.452
2.458
2.518
2.509
2.550
LS Mean Change
0.147(0.036)
0.212(0.036)
0.217(0.035)
0.278(0.036)
0.269(0.035)
0.309(0.035)
(SE)
0.064
0.069
0.130
(-0.036,0.164) (-0.029,0.168) (0.030,0.230)
0.208
0.169
0.011
0.121
(0.023,0.220)
0.016
0.162
(0.062,0.261)
0.001
275
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Table 7.5
Summary of Trough FEV1 (L) (LOCF)
Per Protocol
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-------------------------------------------------------------------------------------------Trough FEV1 (L)
n
89
92
94
93
92
96
Mean
2.330
2.527
2.565
2.559
2.457
2.478
SD
0.8029
0.9228
0.7730
0.7753
0.6990
0.6418
Median
2.238
2.403
2.448
2.411
2.350
2.381
Min.
0.92
0.66
1.25
1.13
1.19
1.20
Max.
4.60
5.02
4.50
4.84
4.03
4.98
276
89
92
94
93
92
96
Mean
SD
Median
Min.
Max.
0.172
0.3948
0.084
-0.77
1.79
0.183
0.4186
0.116
-0.70
1.45
0.235
0.3597
0.187
-0.68
1.80
0.262
0.3884
0.209
-0.69
1.71
0.312
0.3028
0.298
-0.29
1.32
0.290
0.2970
0.244
-0.23
1.23
CONFIDENTIAL
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Table 7.6
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF)
Per Protocol
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.009
Estimate of Slope
95% C.I.
2.212 mL/mcg
(0.557, 3.867)
CONFIDENTIAL
277
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Table 7.7
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Per Protocol
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-----------------------------------------------------------------------------------------------------------n
89
92
94
93
92
96
LS Mean
2.402
2.447
2.478
2.519
2.536
2.537
LS Mean Change
0.157(0.037)
0.203(0.036)
0.233(0.035)
0.275(0.035)
0.292(0.036)
0.293(0.035)
(SE)
0.046
0.076
0.118
(-0.056,0.148) (-0.024,0.176) (0.017,0.218)
0.375
0.134
0.022
0.135
(0.035,0.234)
0.008
0.135
(0.035,0.235)
0.008
278
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.8
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (Repeated Measures)
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.004
Estimate of Slope
95% C.I.
2.352 mL/mcg
(0.748, 3.957)
CONFIDENTIAL
279
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, dose, visit, visit by baseline interaction and visit by dose interaction
Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.383
2.450
2.433
2.465
2.455
2.498
LS Mean Change
0.142(0.034)
0.210(0.033)
0.192(0.033)
0.225(0.033)
0.214(0.033)
0.258(0.033)
(SE)
0.068
0.050
0.082
0.072
0.116
(-0.026,0.162) (-0.043,0.143) (-0.011,0.176) (-0.020,0.165) (0.022,0.209)
0.158
0.292
0.085
0.126
0.015
280
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.391
2.452
2.417
2.456
2.463
2.499
LS Mean Change
0.150(0.036)
0.212(0.035)
0.177(0.035)
0.216(0.035)
0.222(0.035)
0.258(0.035)
(SE)
0.061
0.026
0.065
0.072
0.108
(-0.038,0.161) (-0.072,0.124) (-0.034,0.164) (-0.026,0.169) (0.010,0.206)
0.224
0.600
0.196
0.150
0.032
281
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.395
2.411
2.412
2.452
2.461
2.522
LS Mean Change
0.154(0.035)
0.171(0.035)
0.172(0.035)
0.212(0.035)
0.221(0.035)
0.282(0.034)
(SE)
0.017
0.018
0.058
0.067
0.128
(-0.082,0.116) (-0.080,0.115) (-0.041,0.156) (-0.030,0.164) (0.030,0.225)
0.741
0.724
0.251
0.178
0.010
282
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)
0.127
(0.031,0.223)
0.010
0.152
(0.056,0.249)
0.002
283
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
102
101
101
100
101
102
Mean
2.220
2.284
2.310
2.303
2.150
2.199
SD
0.6826
0.7898
0.6385
0.6632
0.6154
0.5953
Median
2.118
2.228
2.351
2.269
2.095
2.173
Min.
0.93
0.79
1.16
0.91
1.01
1.12
Max.
4.47
3.99
3.64
4.12
3.84
4.08
CONFIDENTIAL
284
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1: 23-24 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
101
101
101
99
100
101
Mean
2.398
2.523
2.517
2.557
2.464
2.513
SD
0.7885
0.9285
0.7657
0.7754
0.7154
0.6408
Median
2.276
2.415
2.528
2.484
2.342
2.509
Min.
1.06
0.83
1.17
1.07
1.03
1.27
Max.
4.58
4.90
4.27
5.00
4.23
4.57
Change from Baseline in FEV1 (L)
101
0.186
0.3811
0.117
-0.39
1.74
101
0.238
0.3608
0.148
-0.44
1.56
101
0.208
0.3070
0.192
-0.55
1.27
99
0.257
0.3593
0.173
-0.22
1.98
100
0.319
0.3453
0.246
-0.33
1.97
101
0.314
0.2564
0.275
-0.60
1.13
CONFIDENTIAL
285
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
95
98
99
97
99
100
Mean
2.332
2.489
2.517
2.520
2.375
2.452
SD
0.7569
0.9000
0.7875
0.7947
0.6751
0.6786
Median
2.273
2.365
2.495
2.426
2.239
2.455
Min.
0.98
0.86
0.93
0.82
1.10
1.20
Max.
4.80
4.74
4.65
5.12
4.03
5.10
Change from Baseline in FEV1 (L)
95
0.155
0.3675
0.049
-0.43
1.66
98
0.197
0.3563
0.128
-0.39
1.53
99
0.194
0.3432
0.117
-0.68
1.18
97
0.216
0.3753
0.151
-0.73
1.73
99
0.225
0.3128
0.189
-0.77
1.13
100
0.254
0.3009
0.202
-0.39
1.10
CONFIDENTIAL
286
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
93
92
95
92
95
98
Mean
2.347
2.562
2.523
2.500
2.400
2.461
SD
0.7816
0.8677
0.7736
0.7822
0.7065
0.6569
Median
2.274
2.399
2.465
2.428
2.262
2.391
Min.
1.00
0.66
1.07
0.87
1.11
1.36
Max.
4.89
4.82
4.44
5.05
3.99
5.20
Change from Baseline in FEV1 (L)
93
0.171
0.3794
0.078
-0.46
1.84
92
0.208
0.3722
0.176
-0.70
1.30
95
0.183
0.3675
0.100
-0.91
1.44
92
0.199
0.3464
0.153
-0.40
1.77
95
0.256
0.3045
0.193
-0.29
1.60
98
0.252
0.3154
0.203
-0.31
1.27
CONFIDENTIAL
287
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
89
86
91
89
94
98
Mean
2.347
2.571
2.563
2.483
2.399
2.485
SD
0.8012
0.8443
0.7555
0.7727
0.6911
0.6755
Median
2.289
2.444
2.541
2.349
2.315
2.470
Min.
0.92
1.27
1.14
1.02
1.16
1.29
Max.
5.07
4.82
4.33
4.90
4.08
4.95
Change from Baseline in FEV1 (L)
89
0.174
0.3840
0.084
-0.60
1.68
86
0.191
0.3676
0.109
-0.63
1.38
91
0.195
0.3309
0.129
-0.39
1.51
89
0.194
0.3241
0.154
-0.69
1.72
94
0.258
0.3176
0.226
-0.43
1.70
98
0.276
0.3229
0.225
-0.28
1.46
CONFIDENTIAL
288
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 6
Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: 23-24 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
87
84
91
88
93
97
Mean
2.365
2.637
2.611
2.556
2.469
2.516
SD
0.7837
0.8704
0.7609
0.7635
0.7051
0.6630
Median
2.286
2.511
2.495
2.415
2.385
2.450
Min.
1.03
1.22
1.25
1.13
1.07
1.42
Max.
4.53
5.02
4.50
4.84
4.03
4.98
Change from Baseline in FEV1 (L)
87
0.186
0.4057
0.084
-0.77
1.79
84
0.254
0.3668
0.147
-0.41
1.45
91
0.243
0.3466
0.186
-0.34
1.80
88
0.269
0.3438
0.205
-0.36
1.71
93
0.318
0.2915
0.297
-0.18
1.32
97
0.302
0.3119
0.245
-0.23
1.23
CONFIDENTIAL
289
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 7.11
Summary of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 by %Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum 1: >=40% - <=65%
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------Trough FEV1 (L)
n
43
44
41
40
46
45
Mean
1.974
1.897
2.121
2.151
2.165
2.200
SD
0.6917
0.6543
0.6599
0.6369
0.6689
0.5461
Median
1.758
1.811
1.924
2.038
2.022
2.107
Min.
1.03
0.66
1.07
1.13
1.07
1.20
Max.
4.16
3.76
4.50
4.09
3.76
3.45
290
43
44
41
40
46
45
Mean
SD
Median
Min.
Max.
0.233
0.4549
0.106
-0.52
1.79
0.159
0.3899
0.152
-0.70
1.45
0.265
0.3790
0.221
-0.91
1.80
0.311
0.4419
0.214
-0.50
1.71
0.322
0.3264
0.302
-0.77
1.32
0.373
0.3183
0.329
-0.19
1.23
CONFIDENTIAL
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 7.11
Summary of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 by %Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum 2: >65% - <=90%
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------Trough FEV1 (L)
n
52
54
58
57
53
55
Mean
2.642
2.972
2.836
2.867
2.663
2.751
SD
0.7210
0.8287
0.7224
0.7505
0.6504
0.6598
Median
2.472
2.837
2.801
2.786
2.612
2.731
Min.
1.26
1.23
1.60
1.65
1.39
1.75
Max.
4.53
5.02
4.35
4.84
4.03
4.98
291
52
54
58
57
53
55
Mean
SD
Median
Min.
Max.
0.105
0.3631
0.042
-0.77
1.20
0.228
0.4080
0.111
-0.57
1.18
0.183
0.3617
0.157
-0.68
0.93
0.238
0.3444
0.199
-0.52
1.71
0.248
0.3315
0.228
-0.60
1.21
0.249
0.2955
0.222
-0.23
1.16
CONFIDENTIAL
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.12
Slope Estimate of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF) at Day 28
by %Predicted FEV1 Stratum
Stratum
------------------------------------------------------------------1: >=40% - <=65%
Estimate of Slope
2.833 mL/mcg
95% C.I.
(0.136, 5.529)
2: >65% - <=90%
Estimate of Slope
95% C.I.
2.222 mL/mcg
(0.085, 4.359)
CONFIDENTIAL
292
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.13
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
44
41
40
46
45
LS Mean
2.450
2.402
2.487
2.559
2.522
2.590
LS Mean Change
0.210(0.057)
0.161(0.056)
0.247(0.057)
0.319(0.057)
0.281(0.054)
0.349(0.055)
(SE)
293
-0.049
0.037
0.109
0.072
0.139
(-0.198,0.100) (-0.113,0.188) (-0.044,0.262) (-0.075,0.218) (-0.009,0.287)
52
2.338
0.098(0.049)
54
2.495
0.254(0.051)
0.156
(0.022,0.291)
58
2.435
0.194(0.048)
57
2.488
0.247(0.049)
0.097
0.149
(-0.035,0.228) (0.018,0.281)
53
2.499
0.259(0.049)
0.161
(0.027,0.295)
55
2.517
0.276(0.049)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
0.178
(0.045,0.312)
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, ,
stratum, treatment and treatment by stratum interaction
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
89
86
85
87
87
86
86
59
59
87
87
87
86
86
2.347
2.326
2.337
2.328
2.331
2.330
2.315
2.434
2.334
2.366
2.375
2.371
2.377
2.361
0.8012
0.7668
0.7873
0.7645
0.7684
0.7774
0.7882
0.7966
0.7574
0.7351
0.7756
0.7584
0.7798
0.7989
2.289
2.266
2.278
2.243
2.239
2.196
2.213
2.382
2.264
2.261
2.276
2.273
2.316
2.260
0.92
0.90
0.85
0.96
0.96
0.89
0.83
1.11
1.00
1.06
1.01
1.03
1.07
0.97
5.07
4.69
4.74
4.63
4.68
4.53
4.52
4.85
4.37
4.32
4.63
4.43
4.46
4.60
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
294
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
Pre-dose
102
2.220
0.6826
2.118
0.93
4.47
15 mins
102
2.310
0.7626
2.203
0.84
4.88
30 mins
99
2.318
0.7810
2.227
0.89
5.11
1 hour
101
2.346
0.7843
2.218
0.87
5.12
2 hours
100
2.351
0.7991
2.273
0.77
5.00
3 hours
101
2.339
0.7660
2.266
0.76
4.97
4 hours
100
2.320
0.7778
2.269
0.70
4.87
6 hours
66
2.412
0.7851
2.353
1.05
4.65
12 hours
66
2.360
0.7995
2.246
0.72
4.78
16 hours
101
2.412
0.8069
2.317
0.83
4.69
20 hours
100
2.423
0.7862
2.314
0.89
4.62
22 hours
101
2.388
0.7908
2.290
1.05
4.71
23 hours
99
2.414
0.7996
2.345
1.08
4.63
24 hours
98
2.375
0.7937
2.219
1.05
4.53
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
86
84
85
85
84
82
84
56
56
84
84
84
84
83
2.571
2.616
2.627
2.654
2.657
2.664
2.636
2.690
2.629
2.693
2.675
2.678
2.653
2.615
0.8443
0.8418
0.8198
0.8553
0.8389
0.8644
0.8556
0.8682
0.8710
0.8673
0.8584
0.8745
0.8658
0.8842
2.444
2.581
2.546
2.485
2.526
2.522
2.477
2.550
2.469
2.522
2.569
2.510
2.474
2.478
1.27
1.32
1.31
1.26
1.30
1.29
1.26
1.24
1.23
1.22
1.15
1.21
1.24
1.19
4.82
4.85
4.87
5.02
5.03
5.05
5.06
5.07
4.96
4.99
5.02
4.96
4.98
5.06
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
295
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------3mcg
101
Day 1
Pre-dose
101
2.284
0.7898
2.228
0.79
3.99
15 mins
97
2.430
0.8621
2.345
0.74
4.51
30 mins
97
2.465
0.8856
2.351
0.73
4.79
1 hour
101
2.466
0.9038
2.258
0.84
4.70
2 hours
101
2.485
0.9342
2.337
0.80
4.72
3 hours
100
2.501
0.9412
2.379
0.92
4.80
4 hours
101
2.486
0.9357
2.374
0.92
4.79
6 hours
67
2.523
0.9637
2.425
0.93
4.90
12 hours
66
2.511
0.9619
2.353
0.91
4.78
16 hours
100
2.518
0.9087
2.402
0.89
4.88
20 hours
99
2.555
0.9347
2.394
0.83
4.91
22 hours
99
2.530
0.9418
2.390
0.80
4.98
23 hours
101
2.516
0.9322
2.422
0.88
4.86
24 hours
98
2.499
0.9137
2.373
0.79
4.95
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
91
90
90
91
91
91
91
61
61
90
91
90
90
91
2.563
2.588
2.592
2.622
2.625
2.645
2.621
2.752
2.688
2.637
2.656
2.628
2.619
2.606
0.7555
0.7577
0.7575
0.7726
0.7738
0.7748
0.7713
0.7770
0.7467
0.7682
0.7676
0.7749
0.7621
0.7667
2.541
2.520
2.512
2.659
2.658
2.598
2.620
2.731
2.635
2.578
2.601
2.564
2.536
2.440
1.14
1.18
1.15
1.16
1.24
1.22
1.19
1.28
1.13
1.24
1.12
1.15
1.28
1.23
4.33
4.37
4.28
4.37
4.38
4.41
4.34
4.21
4.25
4.45
4.61
4.60
4.57
4.44
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
296
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
Pre-dose
101
2.310
0.6385
2.351
1.16
3.64
15 mins
99
2.410
0.7211
2.392
1.11
4.03
30 mins
100
2.455
0.7318
2.399
1.16
4.09
1 hour
101
2.483
0.7388
2.433
1.18
4.31
2 hours
101
2.510
0.7369
2.538
1.22
4.39
3 hours
99
2.507
0.7649
2.483
1.14
4.44
4 hours
101
2.511
0.7526
2.485
1.19
4.32
6 hours
69
2.649
0.7653
2.673
1.24
4.32
12 hours
70
2.567
0.8007
2.516
0.85
4.46
16 hours
101
2.572
0.7601
2.596
1.23
4.43
20 hours
101
2.541
0.7536
2.544
1.14
4.29
22 hours
101
2.528
0.7625
2.499
1.15
4.29
23 hours
101
2.506
0.7681
2.485
1.17
4.47
24 hours
101
2.528
0.7694
2.519
1.15
4.17
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
89
87
88
88
88
88
88
64
64
88
87
85
87
87
2.483
2.530
2.536
2.558
2.568
2.591
2.576
2.617
2.520
2.582
2.581
2.528
2.563
2.546
0.7727
0.7837
0.7935
0.8028
0.8039
0.7934
0.7983
0.7958
0.8031
0.7560
0.7691
0.7380
0.7646
0.7661
2.349
2.424
2.427
2.435
2.434
2.440
2.454
2.525
2.436
2.489
2.468
2.427
2.434
2.440
1.02
1.14
1.07
1.16
1.16
1.15
1.15
1.02
1.01
1.16
1.07
1.12
1.11
1.14
4.90
5.00
5.04
5.10
5.02
4.92
4.86
4.78
4.80
5.00
4.90
4.94
4.88
4.81
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
297
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------12.5mcg
100
Day 1
Pre-dose
100
2.303
0.6632
2.269
0.91
4.12
15 mins
99
2.481
0.8050
2.388
1.03
4.84
30 mins
99
2.535
0.8160
2.414
1.04
4.93
1 hour
99
2.569
0.7981
2.436
1.02
4.94
2 hours
98
2.589
0.8139
2.499
1.08
4.99
3 hours
99
2.603
0.8068
2.477
1.00
5.07
4 hours
99
2.589
0.8009
2.490
1.00
5.18
6 hours
71
2.615
0.7589
2.553
1.36
4.75
12 hours
70
2.549
0.7824
2.481
1.29
4.96
16 hours
99
2.572
0.8067
2.508
1.09
5.07
20 hours
99
2.570
0.7923
2.493
1.03
4.94
22 hours
96
2.559
0.7584
2.487
1.03
4.93
23 hours
98
2.568
0.7923
2.512
1.08
5.03
24 hours
97
2.543
0.7741
2.473
1.06
4.97
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
94
93
93
93
93
92
93
56
56
93
93
93
93
93
2.399
2.457
2.487
2.511
2.513
2.511
2.503
2.500
2.406
2.476
2.504
2.492
2.465
2.474
0.6911
0.6931
0.7063
0.7102
0.6942
0.7085
0.6899
0.7085
0.6966
0.6796
0.6993
0.7151
0.7030
0.7110
2.315
2.334
2.358
2.396
2.370
2.359
2.380
2.308
2.323
2.270
2.401
2.460
2.358
2.412
1.16
1.16
1.12
1.24
1.23
1.24
1.22
1.18
1.13
1.34
1.15
1.02
0.99
1.15
4.08
4.05
4.15
4.10
4.10
4.07
4.10
4.08
4.07
4.08
4.23
4.01
4.06
4.03
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
298
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
Pre-dose
101
2.150
0.6154
2.095
1.01
3.84
15 mins
98
2.410
0.7122
2.238
1.06
4.08
30 mins
98
2.451
0.7128
2.388
1.08
4.08
1 hour
101
2.462
0.7138
2.384
1.07
4.16
2 hours
101
2.490
0.7246
2.363
0.97
4.30
3 hours
98
2.532
0.7401
2.352
1.04
4.33
4 hours
100
2.505
0.7321
2.378
0.99
4.30
6 hours
62
2.512
0.7679
2.336
1.01
4.29
12 hours
62
2.432
0.7847
2.228
1.06
4.07
16 hours
101
2.512
0.7218
2.334
1.20
4.55
20 hours
101
2.491
0.7256
2.318
1.09
4.35
22 hours
100
2.471
0.7071
2.304
1.02
4.16
23 hours
99
2.472
0.7128
2.353
1.07
4.10
24 hours
98
2.467
0.7314
2.345
1.00
4.36
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)
Day 28
98
94
97
97
97
98
98
57
58
97
97
94
97
96
2.485
2.519
2.530
2.568
2.577
2.569
2.553
2.518
2.494
2.539
2.557
2.521
2.523
2.505
0.6755
0.6897
0.6533
0.6757
0.6811
0.6728
0.6702
0.6731
0.7353
0.6764
0.6611
0.6558
0.6812
0.6574
2.470
2.507
2.498
2.539
2.570
2.579
2.537
2.472
2.420
2.484
2.512
2.413
2.426
2.409
1.29
1.34
1.24
1.32
1.35
1.43
1.35
1.32
1.15
1.23
1.23
1.32
1.32
1.41
4.95
4.98
4.82
4.84
5.03
4.91
4.88
4.87
4.99
5.17
4.74
4.93
5.07
4.90
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
299
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------50mcg
102
Day 1
Pre-dose
102
2.199
0.5953
2.173
1.12
4.08
15 mins
98
2.428
0.6583
2.340
1.10
4.98
30 mins
97
2.491
0.6586
2.431
1.17
4.91
1 hour
101
2.527
0.6604
2.486
1.28
5.03
2 hours
100
2.561
0.7003
2.466
1.20
5.22
3 hours
100
2.570
0.6776
2.553
1.27
5.05
4 hours
99
2.562
0.6844
2.548
1.28
5.18
6 hours
59
2.549
0.7025
2.545
1.20
4.64
12 hours
60
2.529
0.7509
2.512
1.04
4.76
16 hours
101
2.561
0.6948
2.546
1.14
5.18
20 hours
99
2.551
0.6897
2.511
1.05
5.07
22 hours
100
2.511
0.6829
2.477
1.19
5.14
23 hours
100
2.523
0.6682
2.486
1.31
4.94
24 hours
99
2.497
0.6298
2.464
1.19
4.24
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 3
Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
15 mins
102
0.090
0.3169
0.009
-0.47
1.65
30 mins
99
0.090
0.3521
-0.001
-0.94
1.59
1 hour
101
0.118
0.3423
0.013
-0.43
1.63
2 hours
100
0.130
0.3490
0.042
-0.52
1.62
3 hours
101
0.112
0.3458
0.025
-0.44
1.72
4 hours
100
0.099
0.3743
0.018
-1.02
1.66
101
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
0.174
0.138
0.146
0.149
0.152
0.166
0.133
0.3840
0.3737
0.3797
0.3728
0.3865
0.3872
0.3693
0.084
0.042
0.094
0.078
0.031
0.085
0.075
-0.60
-0.55
-0.67
-0.71
-0.74
-0.92
-0.79
1.68
1.71
1.74
1.57
1.62
1.79
1.66
97
97
101
101
100
101
0.121
0.152
0.182
0.201
0.221
0.201
0.2668
0.2930
0.3126
0.3448
0.3515
0.3380
0.069
0.074
0.084
0.099
0.115
0.110
-0.31
-0.23
-0.27
-0.42
-0.39
-0.28
1.15
1.16
1.42
1.43
1.49
1.34
86
84
85
85
84
82
84
0.191
0.226
0.237
0.263
0.275
0.267
0.254
0.3676
0.3304
0.3302
0.3555
0.3515
0.3494
0.3408
0.109
0.127
0.147
0.162
0.178
0.179
0.170
-0.63
-0.44
-0.43
-0.27
-0.47
-0.38
-0.41
1.38
1.40
1.33
1.48
1.48
1.52
1.52
CONFIDENTIAL
3mcg
89
86
85
87
87
86
86
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
300
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 3
Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
15 mins
99
0.098
0.2312
0.078
-0.40
1.18
30 mins
100
0.148
0.2673
0.117
-0.40
1.39
1 hour
101
0.174
0.2772
0.117
-0.36
1.36
2 hours
101
0.200
0.2885
0.137
-0.25
1.43
3 hours
99
0.210
0.3070
0.167
-0.48
1.40
4 hours
101
0.201
0.2912
0.157
-0.47
1.30
0.195
0.221
0.226
0.254
0.257
0.278
0.253
0.3309
0.3288
0.3320
0.3422
0.3464
0.3408
0.3367
0.129
0.155
0.166
0.191
0.198
0.205
0.226
-0.39
-0.36
-0.33
-0.35
-0.31
-0.25
-0.45
1.51
1.33
1.49
1.44
1.68
1.67
1.64
12.5mcg
100
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
99
99
99
98
99
99
0.179
0.234
0.270
0.292
0.304
0.290
0.3562
0.3641
0.3335
0.3620
0.3398
0.3498
0.123
0.180
0.211
0.228
0.232
0.236
-0.46
-0.27
-0.31
-0.21
-0.15
-0.26
1.92
1.95
1.95
2.05
1.97
2.00
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
89
87
88
88
88
88
88
0.194
0.238
0.250
0.272
0.281
0.305
0.290
0.3241
0.3260
0.3311
0.3336
0.3345
0.3263
0.3251
0.154
0.198
0.219
0.248
0.215
0.251
0.235
-0.69
-0.39
-0.34
-0.24
-0.26
-0.28
-0.36
1.72
1.61
1.57
1.61
1.65
1.60
1.53
CONFIDENTIAL
91
90
90
91
91
91
91
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
301
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 3
Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
15 mins
98
0.253
0.3088
0.180
-0.32
1.89
30 mins
98
0.293
0.3241
0.231
-0.48
1.89
1 hour
101
0.312
0.3231
0.257
-0.32
1.95
2 hours
101
0.340
0.3397
0.277
-0.26
2.12
3 hours
98
0.392
0.3527
0.313
-0.19
2.05
4 hours
100
0.355
0.3423
0.312
-0.22
2.01
102
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
0.258
0.306
0.337
0.360
0.362
0.368
0.353
0.3176
0.3057
0.3123
0.3266
0.2992
0.3053
0.2957
0.226
0.253
0.278
0.324
0.328
0.347
0.342
-0.43
-0.39
-0.28
-0.23
-0.17
-0.28
-0.46
1.70
1.66
1.77
1.68
1.45
1.48
1.33
98
97
101
100
100
99
0.233
0.293
0.331
0.368
0.374
0.367
0.2177
0.2067
0.2250
0.2651
0.2563
0.2730
0.213
0.272
0.292
0.317
0.324
0.331
-0.56
-0.17
-0.29
-0.20
-0.30
-0.26
0.90
0.88
0.95
1.51
1.22
1.33
98
94
97
97
97
98
98
0.276
0.315
0.319
0.361
0.366
0.360
0.343
0.3229
0.3299
0.3271
0.3365
0.3499
0.3395
0.3365
0.225
0.256
0.259
0.319
0.281
0.304
0.290
-0.28
-0.48
-0.41
-0.32
-0.34
-0.47
-0.45
1.46
1.57
1.50
1.52
1.49
1.46
1.56
CONFIDENTIAL
50mcg
94
93
93
93
93
92
93
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
302
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 3
Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
15 mins
102
4.17
15.118
0.36
-26.5
79.6
30 mins
99
4.22
15.706
-0.06
-28.4
79.0
1 hour
101
5.39
15.813
0.73
-19.6
75.6
2 hours
100
5.70
16.243
1.73
-23.8
80.5
3 hours
101
5.20
15.703
1.23
-25.2
75.1
4 hours
100
4.77
16.965
0.77
-30.8
82.4
101
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
8.46
6.94
7.13
7.68
7.78
8.16
6.29
18.127
17.669
17.401
17.403
18.283
17.838
16.938
3.43
2.92
4.05
3.58
2.90
3.49
3.03
-23.6
-19.3
-22.2
-25.3
-25.5
-31.8
-27.3
79.5
70.9
76.0
76.1
80.6
82.2
77.1
97
97
101
101
100
101
5.43
6.52
8.01
8.56
9.56
8.49
11.936
12.578
13.195
14.584
14.829
14.010
3.38
3.67
4.42
5.03
5.71
5.60
-15.3
-9.3
-10.1
-13.6
-21.1
-14.8
48.3
46.5
60.8
65.8
66.8
57.6
86
84
85
85
84
82
84
9.20
10.66
11.38
12.13
13.08
12.25
11.77
16.611
14.742
15.324
16.201
16.755
16.435
15.826
5.42
5.97
6.97
7.76
7.38
8.88
8.59
-32.8
-14.9
-13.7
-12.2
-21.1
-17.0
-18.3
59.7
60.3
59.0
72.6
65.6
72.8
65.7
CONFIDENTIAL
3mcg
89
86
85
87
87
86
86
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
303
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 3
Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
15 mins
99
3.92
9.764
3.49
-19.9
43.7
30 mins
100
6.36
11.142
5.35
-14.1
51.4
1 hour
101
7.46
11.410
5.71
-12.9
50.2
2 hours
101
8.75
12.055
6.97
-10.6
53.1
3 hours
99
9.01
13.022
8.50
-29.5
52.0
4 hours
101
8.65
12.002
7.72
-16.1
48.1
8.37
9.53
9.82
10.85
11.00
11.84
10.77
13.663
13.450
13.765
13.967
14.377
14.082
13.813
5.46
7.21
6.79
10.06
8.02
9.13
9.69
-17.2
-12.9
-15.3
-18.4
-16.4
-10.4
-18.0
55.8
49.2
55.1
53.3
62.3
61.9
60.6
12.5mcg
100
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
99
99
99
98
99
99
7.62
10.03
11.82
12.89
13.26
12.87
14.270
14.776
13.778
15.295
13.596
14.277
5.41
7.73
9.64
9.72
10.26
9.54
-18.0
-15.0
-14.6
-11.1
-7.0
-9.2
80.7
77.6
78.3
86.5
77.0
77.8
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
89
87
88
88
88
88
88
8.64
10.71
11.10
12.03
12.48
13.75
12.95
13.464
14.253
14.474
14.691
14.721
14.868
14.483
6.33
8.41
10.11
9.85
9.71
11.04
10.67
-24.9
-14.3
-14.9
-15.4
-13.2
-14.2
-13.6
57.5
65.3
66.8
71.4
70.6
68.3
76.5
CONFIDENTIAL
91
90
90
91
91
91
91
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
304
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 3
Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)
Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
15 mins
98
12.33
15.169
9.21
-13.9
103.6
30 mins
98
14.27
15.835
11.47
-21.0
104.0
1 hour
101
15.38
16.112
12.62
-14.0
107.2
2 hours
101
16.74
17.250
14.61
-11.7
116.2
3 hours
98
19.25
17.456
16.31
-7.8
112.3
4 hours
100
17.44
17.104
15.02
-10.3
110.5
102
Day 1
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
Day 28
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
13.26
15.50
16.92
18.15
18.28
18.48
17.88
14.961
14.842
15.168
16.057
15.204
14.858
15.019
10.51
12.74
14.57
15.26
14.71
17.21
16.64
-15.7
-14.3
-10.1
-9.6
-6.0
-10.1
-18.7
71.4
69.8
74.3
70.6
60.8
62.3
56.9
98
97
101
100
100
99
11.10
13.95
16.04
17.65
18.17
17.89
9.882
9.972
11.448
12.459
12.951
13.378
10.29
13.28
14.04
14.87
16.35
16.99
-16.7
-8.3
-14.7
-10.7
-14.8
-13.3
39.2
43.9
50.3
65.7
67.1
66.6
98
94
97
97
97
98
98
13.70
15.62
16.09
17.93
18.19
17.95
17.18
15.458
15.946
16.123
16.541
17.167
17.237
17.197
11.15
13.14
12.87
15.53
14.55
14.25
13.43
-13.6
-24.2
-12.4
-13.4
-11.9
-22.7
-21.9
71.5
67.9
63.4
72.4
75.3
75.2
83.9
CONFIDENTIAL
50mcg
94
93
93
93
93
92
93
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
305
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
15 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.323
2.377
2.342
2.424
2.496
2.474
LS Mean Change
0.079(0.027)
0.133(0.027)
0.098(0.027)
0.180(0.027)
0.252(0.027)
0.230(0.027)
(SE)
0.054
0.019
0.101
(-0.022,0.130) (-0.056,0.094) (0.025,0.176)
0.173
(0.098,0.248)
0.150
(0.075,0.226)
306
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
30 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.324
2.407
2.389
2.481
2.530
2.535
LS Mean Change
0.080(0.029)
0.163(0.029)
0.145(0.029)
0.237(0.029)
0.286(0.029)
0.291(0.029)
(SE)
0.083
(0.003,0.163)
0.065
0.157
(-0.015,0.144) (0.078,0.237)
0.206
(0.127,0.286)
0.211
(0.131,0.291)
307
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
1 Hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.352
2.441
2.415
2.527
2.553
2.576
LS Mean Change
0.108(0.029)
0.197(0.029)
0.171(0.029)
0.283(0.029)
0.309(0.029)
0.332(0.029)
(SE)
0.089
(0.009,0.169)
0.063
0.176
(-0.016,0.143) (0.096,0.255)
0.201
(0.122,0.280)
0.224
(0.145,0.304)
308
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
2 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.362
2.459
2.440
2.552
2.582
2.614
LS Mean Change
0.118(0.031)
0.215(0.031)
0.196(0.031)
0.308(0.031)
0.338(0.031)
0.370(0.031)
(SE)
0.097
(0.011,0.182)
0.078
0.189
(-0.007,0.163) (0.104,0.275)
0.219
(0.135,0.304)
0.251
(0.166,0.337)
309
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
3 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.345
2.478
2.448
2.560
2.626
2.619
LS Mean Change
0.101(0.031)
0.234(0.031)
0.203(0.031)
0.316(0.031)
0.382(0.031)
0.375(0.031)
(SE)
0.133
(0.047,0.218)
0.102
(0.017,0.187)
0.215
(0.130,0.300)
0.280
(0.196,0.365)
0.274
(0.188,0.359)
310
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
4 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.332
2.460
2.442
2.547
2.599
2.611
LS Mean Change
0.088(0.031)
0.216(0.031)
0.198(0.031)
0.303(0.031)
0.355(0.031)
0.367(0.031)
(SE)
0.127
(0.041,0.214)
0.109
(0.023,0.196)
0.215
(0.128,0.301)
0.266
(0.181,0.352)
0.278
(0.192,0.365)
311
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
6 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.365
2.473
2.484
2.537
2.596
2.609
LS Mean Change
0.121(0.032)
0.229(0.033)
0.240(0.032)
0.292(0.032)
0.352(0.033)
0.365(0.033)
(SE)
0.108
(0.017,0.198)
0.119
(0.029,0.209)
0.172
(0.082,0.261)
0.231
(0.141,0.321)
0.244
(0.153,0.335)
312
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
12 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.334
2.447
2.414
2.466
2.526
2.597
LS Mean Change
0.090(0.037)
0.202(0.037)
0.170(0.036)
0.222(0.037)
0.282(0.037)
0.353(0.037)
(SE)
0.112
(0.010,0.215)
0.080
0.132
(-0.021,0.181) (0.030,0.233)
0.192
(0.089,0.294)
0.263
(0.161,0.366)
313
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
16 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.430
2.504
2.504
2.529
2.602
2.605
LS Mean Change
0.186(0.033)
0.260(0.033)
0.260(0.033)
0.285(0.033)
0.358(0.033)
0.361(0.033)
(SE)
0.074
0.074
0.099
(-0.018,0.166) (-0.017,0.165) (0.008,0.191)
0.172
(0.081,0.263)
0.175
(0.084,0.267)
314
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
20 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.444
2.526
2.472
2.528
2.581
2.585
LS Mean Change
0.200(0.033)
0.282(0.033)
0.228(0.033)
0.284(0.033)
0.337(0.033)
0.341(0.033)
(SE)
0.083
0.029
0.084
0.138
(-0.009,0.174) (-0.062,0.120) (-0.007,0.175) (0.047,0.229)
0.141
(0.050,0.232)
315
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
22 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.410
2.514
2.460
2.543
2.564
2.549
LS Mean Change
0.166(0.032)
0.270(0.032)
0.215(0.032)
0.299(0.032)
0.320(0.032)
0.305(0.032)
(SE)
0.104
(0.016,0.193)
0.050
0.133
(-0.038,0.138) (0.045,0.222)
0.155
(0.067,0.242)
0.139
(0.051,0.228)
316
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
23 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.426
2.491
2.438
2.523
2.557
2.571
LS Mean Change
0.182(0.032)
0.247(0.032)
0.194(0.032)
0.279(0.032)
0.313(0.032)
0.327(0.032)
(SE)
0.065
0.013
0.097
(-0.024,0.155) (-0.076,0.102) (0.008,0.187)
0.131
(0.042,0.221)
0.145
(0.056,0.235)
317
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
24 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.407
2.506
2.461
2.507
2.553
2.541
LS Mean Change
0.162(0.032)
0.262(0.033)
0.217(0.032)
0.263(0.033)
0.309(0.032)
0.297(0.032)
(SE)
0.099
(0.009,0.190)
0.055
0.100
(-0.035,0.145) (0.010,0.190)
0.147
(0.057,0.236)
0.135
(0.045,0.225)
318
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Pre-Dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.416
2.466
2.447
2.469
2.504
2.535
LS Mean Change
0.158(0.035)
0.208(0.035)
0.189(0.034)
0.211(0.034)
0.246(0.034)
0.277(0.033)
(SE)
0.050
0.031
0.053
0.088
0.119
(-0.047,0.147) (-0.064,0.127) (-0.043,0.149) (-0.006,0.182) (0.025,0.213)
319
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
15 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.366
2.497
2.469
2.509
2.553
2.569
LS Mean Change
0.108(0.034)
0.238(0.034)
0.210(0.033)
0.251(0.033)
0.295(0.033)
0.311(0.032)
(SE)
0.131
(0.036,0.225)
0.103
(0.010,0.195)
0.143
(0.050,0.236)
0.187
(0.096,0.279)
0.203
(0.112,0.294)
320
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
30 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.374
2.510
2.478
2.518
2.583
2.573
LS Mean Change
0.116(0.034)
0.252(0.034)
0.220(0.033)
0.260(0.034)
0.325(0.033)
0.315(0.032)
(SE)
0.135
(0.041,0.230)
0.104
(0.011,0.197)
0.143
(0.050,0.237)
0.209
(0.117,0.301)
0.199
(0.107,0.290)
321
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
1 Hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.379
2.534
2.505
2.539
2.609
2.619
LS Mean Change
0.121(0.034)
0.276(0.035)
0.247(0.034)
0.281(0.034)
0.350(0.033)
0.361(0.033)
(SE)
0.155
(0.058,0.252)
0.126
(0.031,0.221)
0.160
(0.064,0.256)
0.229
(0.135,0.323)
0.240
(0.146,0.333)
322
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
2 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.381
2.541
2.509
2.549
2.609
2.618
LS Mean Change
0.123(0.034)
0.283(0.035)
0.251(0.034)
0.291(0.034)
0.351(0.033)
0.360(0.033)
(SE)
0.160
(0.063,0.256)
0.128
(0.033,0.223)
0.168
(0.073,0.264)
0.228
(0.134,0.322)
0.237
(0.144,0.331)
323
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
3 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.397
2.533
2.528
2.573
2.617
2.619
LS Mean Change
0.139(0.034)
0.274(0.035)
0.270(0.034)
0.314(0.034)
0.358(0.033)
0.361(0.032)
(SE)
0.136
(0.040,0.232)
0.131
(0.037,0.225)
0.176
(0.081,0.271)
0.220
(0.127,0.313)
0.223
(0.130,0.315)
324
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
4 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.365
2.519
2.504
2.558
2.601
2.603
LS Mean Change
0.107(0.034)
0.260(0.034)
0.246(0.033)
0.300(0.033)
0.343(0.033)
0.344(0.032)
(SE)
0.154
(0.059,0.248)
0.139
(0.047,0.231)
0.193
(0.100,0.286)
0.236
(0.145,0.328)
0.238
(0.147,0.329)
325
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
6 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.418
2.554
2.516
2.538
2.592
2.574
LS Mean Change
0.160(0.035)
0.296(0.036)
0.257(0.035)
0.280(0.035)
0.333(0.035)
0.315(0.034)
(SE)
0.136
(0.037,0.235)
0.098
(0.001,0.194)
0.120
(0.023,0.217)
0.174
(0.077,0.270)
0.155
(0.059,0.252)
326
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
12 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.320
2.500
2.458
2.472
2.487
2.551
LS Mean Change
0.061(0.038)
0.242(0.039)
0.200(0.038)
0.214(0.038)
0.229(0.038)
0.293(0.037)
(SE)
0.181
(0.072,0.289)
0.138
(0.032,0.244)
0.152
(0.046,0.258)
0.167
(0.061,0.273)
0.231
(0.126,0.337)
327
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
16 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.415
2.581
2.529
2.564
2.570
2.583
LS Mean Change
0.157(0.035)
0.323(0.036)
0.271(0.035)
0.306(0.035)
0.312(0.034)
0.325(0.034)
(SE)
0.166
(0.066,0.266)
0.114
(0.016,0.211)
0.149
(0.051,0.248)
0.154
(0.058,0.251)
0.168
(0.072,0.264)
328
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
20 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.425
2.561
2.542
2.573
2.599
2.602
LS Mean Change
0.167(0.035)
0.303(0.036)
0.284(0.035)
0.315(0.035)
0.341(0.034)
0.344(0.033)
(SE)
0.136
(0.037,0.235)
0.117
(0.020,0.214)
0.148
(0.050,0.246)
0.174
(0.078,0.270)
0.177
(0.081,0.273)
329
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
22 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.422
2.563
2.515
2.539
2.588
2.542
LS Mean Change
0.164(0.035)
0.305(0.035)
0.257(0.034)
0.281(0.035)
0.330(0.034)
0.284(0.033)
(SE)
0.141
(0.043,0.238)
0.093
0.117
(-0.003,0.188) (0.021,0.213)
0.166
(0.072,0.260)
0.120
(0.026,0.214)
330
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
23 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.428
2.538
2.501
2.539
2.560
2.568
LS Mean Change
0.170(0.035)
0.280(0.036)
0.243(0.034)
0.280(0.035)
0.302(0.034)
0.310(0.033)
(SE)
0.110
(0.012,0.209)
0.074
0.111
(-0.023,0.170) (0.013,0.208)
0.132
(0.037,0.228)
0.140
(0.045,0.236)
331
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
24 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.403
2.506
2.490
2.538
2.570
2.555
LS Mean Change
0.144(0.035)
0.248(0.036)
0.232(0.034)
0.280(0.035)
0.312(0.034)
0.297(0.033)
(SE)
0.103
(0.005,0.201)
0.088
0.135
(-0.009,0.184) (0.038,0.232)
0.168
(0.072,0.263)
0.152
(0.058,0.247)
332
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.19
Summary of Weighted Mean Change from Baseline in 24 hour Serial Clinic FEV1 (L)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
101
100
101
99
100
100
Mean
0.150
0.219
0.217
0.264
0.338
0.352
SD
0.3384
0.3321
0.2779
0.3354
0.3254
0.2546
Median
0.045
0.119
0.191
0.202
0.296
0.302
Min.
-0.24
-0.28
-0.28
-0.18
-0.39
-0.18
Max.
1.68
1.41
1.32
1.98
1.97
1.28
Day 28
87
0.166
0.3661
0.100
-0.58
1.76
83
0.281
0.3444
0.162
-0.39
1.56
91
0.258
0.3175
0.219
-0.33
1.60
88
0.272
0.3093
0.218
-0.28
1.53
93
0.327
0.2756
0.344
-0.25
1.20
97
0.324
0.3231
0.242
-0.32
1.51
CONFIDENTIAL
333
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.20
Statistical Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
All Subjects, including 6-12 hour time points
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
101
100
101
0.137(0.029)
0.239(0.029)
0.215(0.029)
0.102
(0.020,0.183)
0.015
0.078
0.130
(-0.003,0.158) (0.049,0.211)
0.059
0.002
0.193
(0.112,0.273)
<0.001
0.215
(0.134,0.296)
<0.001
334
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
87
0.149(0.032)
83
0.300(0.033)
0.151
(0.059,0.242)
0.001
91
0.253(0.031)
0.103
(0.014,0.192)
0.023
88
0.292(0.032)
0.142
(0.052,0.232)
0.002
93
0.315(0.031)
0.165
(0.077,0.253)
<0.001
97
0.321(0.031)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
99
100
100
0.267(0.029)
0.330(0.029)
0.352(0.029)
0.172
(0.084,0.260)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.21
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
All Subjects excluding 6-12 hour time points
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
101
100
101
0.144(0.029)
0.244(0.029)
0.220(0.029)
0.099
(0.017,0.181)
0.018
0.076
0.135
(-0.006,0.157) (0.053,0.216)
0.068
0.001
0.199
(0.118,0.280)
<0.001
0.207
(0.126,0.289)
<0.001
335
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
87
0.153(0.033)
83
0.305(0.033)
0.152
(0.060,0.244)
0.001
91
0.259(0.032)
0.106
(0.017,0.195)
0.020
88
0.309(0.032)
0.155
(0.065,0.246)
<0.001
93
0.328(0.031)
0.175
(0.086,0.263)
<0.001
97
0.330(0.031)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
99
100
100
0.279(0.029)
0.343(0.029)
0.352(0.029)
0.177
(0.088,0.265)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.22
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Subset of Subjects who had the 6-12 hour time points measured. All time points included
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
68
0.121(0.037)
0.159
(0.056,0.263)
0.003
70
0.226(0.036)
0.104
(0.002,0.206)
0.045
71
0.259(0.036)
0.138
(0.036,0.239)
0.008
63
0.366(0.038)
0.245
(0.140,0.350)
<0.001
60
0.350(0.039)
0.229
(0.122,0.336)
<0.001
336
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
60
0.135(0.040)
56
0.340(0.042)
0.205
(0.090,0.320)
<0.001
61
0.276(0.040)
0.140
(0.028,0.252)
0.014
65
0.274(0.039)
0.138
(0.028,0.249)
0.014
57
0.366(0.042)
0.231
(0.116,0.345)
<0.001
58
0.327(0.041)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
67
0.281(0.037)
0.191
(0.077,0.306)
0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Note: Subjects are included if they have either a 6hr or 12hr assessment on day 1 or day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.23
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Subset of Subjects who had 6-12 hour time points measured, excluding 6-12 hour time points
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
68
0.132(0.037)
0.157
(0.052,0.261)
0.004
70
0.233(0.037)
71
0.276(0.036)
0.100
0.143
(-0.003,0.203) (0.041,0.246)
0.056
0.006
63
0.386(0.039)
0.253
(0.148,0.359)
<0.001
60
0.349(0.040)
0.217
(0.109,0.324)
<0.001
337
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
60
0.141(0.041)
56
0.348(0.042)
0.207
(0.091,0.323)
<0.001
61
0.285(0.040)
0.143
(0.031,0.256)
0.013
65
0.297(0.039)
0.156
(0.045,0.267)
0.006
57
0.389(0.042)
0.248
(0.133,0.363)
<0.001
58
0.339(0.041)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
67
0.289(0.038)
0.198
(0.083,0.313)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Note: Subjects are included if they have either a 6hr or 12hr assessment on day 1 or day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.24
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Observations without rescue medication
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
89
0.134(0.032)
0.113
(0.027,0.200)
0.010
95
0.224(0.030)
0.090
(0.004,0.176)
0.040
94
0.269(0.031)
0.135
(0.049,0.222)
0.002
97
0.333(0.030)
0.199
(0.114,0.285)
<0.001
95
0.359(0.031)
0.226
(0.139,0.312)
<0.001
338
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
77
0.150(0.035)
79
0.306(0.035)
0.157
(0.060,0.253)
0.002
88
0.252(0.032)
0.103
(0.009,0.196)
0.031
87
0.288(0.033)
0.138
(0.044,0.233)
0.004
92
0.319(0.032)
0.169
(0.077,0.262)
<0.001
96
0.323(0.031)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
96
0.247(0.030)
0.174
(0.082,0.266)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.25
Summary of Post-salbutamol/albuterol FEV1 (L)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Screening
n
102
101
101
100
101
102
Mean
2.767
2.775
2.806
2.792
2.668
2.702
SD
0.8004
0.9468
0.7814
0.7369
0.7027
0.7095
Median
2.676
2.654
2.789
2.693
2.555
2.675
Min.
1.18
1.26
1.45
1.32
1.32
1.07
Max.
5.26
5.17
4.59
4.81
4.23
5.05
n
Mean
SD
Median
Min.
Max.
97
2.713
0.8589
2.661
1.15
5.30
97
2.754
0.9460
2.610
0.87
5.25
98
2.731
0.8000
2.718
1.33
4.66
99
2.744
0.8027
2.639
1.15
5.03
96
2.640
0.7476
2.498
1.27
4.34
98
2.658
0.7010
2.643
1.34
5.21
Day 28
n
Mean
SD
Median
Min.
Max.
84
2.640
0.8338
2.610
1.16
5.16
80
2.813
0.9109
2.660
1.27
5.18
89
2.804
0.7983
2.709
1.40
4.73
86
2.690
0.7978
2.543
1.23
5.08
88
2.577
0.7293
2.464
1.11
4.14
93
2.625
0.6895
2.539
1.43
4.96
CONFIDENTIAL
339
Day 1
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.26
Summary of Post-salbutamol/albuterol FEV1 (L) Differences
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Day 28 - Day 1
n
83
80
87
86
86
92
Mean
-0.035
-0.040
-0.015
-0.019
-0.056
-0.050
SD
0.1784
0.2213
0.2005
0.1858
0.2401
0.2229
Median
-0.029
-0.026
-0.029
-0.018
-0.047
-0.058
Min.
-0.46
-0.78
-0.45
-0.61
-1.37
-0.48
Max.
0.37
0.71
0.61
0.51
0.56
0.91
n
Mean
SD
Median
Min.
Max.
97
-0.028
0.2788
-0.038
-0.99
0.74
97
-0.013
0.3406
0.016
-0.96
1.28
98
-0.062
0.2928
-0.074
-0.94
0.76
99
-0.033
0.2963
-0.050
-0.97
1.37
96
-0.009
0.2505
0.005
-1.05
0.84
98
-0.054
0.2548
-0.030
-1.13
0.47
Day 28 - Screening
n
Mean
SD
Median
Min.
Max.
84
-0.053
0.3026
-0.062
-1.20
0.80
80
-0.048
0.3558
-0.045
-1.44
1.11
89
-0.057
0.2780
-0.064
-0.59
1.33
86
-0.062
0.3111
-0.091
-0.94
1.50
88
-0.068
0.2635
-0.034
-1.33
0.48
93
-0.104
0.2509
-0.072
-0.80
0.68
CONFIDENTIAL
340
Day 1 - Screening
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.27
Statistical Analysis of difference in post-salbutamol/albuterol FEV1 (L)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28 - Day 1
n
83
80
87
86
86
92
LS Mean (SE)
-0.039(0.023) -0.035(0.024) -0.012(0.023) -0.017(0.023) -0.062(0.023) -0.049(0.022)
Column vs Placebo
Difference
95% C.I.
p-value
97
-0.040(0.028)
Column vs Placebo
Difference
95% C.I.
p-value
Day 28 Screening
n
LS Mean (SE)
98
-0.061(0.028)
99
-0.029(0.028)
96
-0.020(0.028)
98
-0.060(0.028)
0.047
-0.021
0.011
0.020
-0.020
(-0.032,0.126) (-0.099,0.057) (-0.067,0.089) (-0.058,0.098) (-0.099,0.058)
0.241
0.598
0.791
0.619
0.613
84
-0.076(0.031)
80
-0.022(0.031)
89
-0.055(0.030)
86
-0.048(0.030)
88
-0.086(0.030)
93
-0.104(0.029)
0.055
0.021
0.029
-0.009
-0.027
(-0.032,0.141) (-0.062,0.105) (-0.056,0.114) (-0.093,0.075) (-0.111,0.056)
0.217
0.615
0.507
0.826
0.519
Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening),
country, sex, age, stratum and treatment
Analysis is of the differences in absolute FEV1 measurements taken post-salbutamol/albuterol
YM2008/00019/00
B2C109575
Column vs Placebo
Difference
95% C.I.
p-value
97
0.008(0.028)
CONFIDENTIAL
341
Day 1 - Screening
n
LS Mean (SE)
0.004
0.027
0.022
-0.023
-0.010
(-0.062,0.069) (-0.037,0.091) (-0.042,0.087) (-0.087,0.041) (-0.074,0.054)
0.916
0.410
0.498
0.482
0.756
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.28
Summary of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
101
Mean
0.243
0.290
0.295
0.387
0.442
0.457
SD
0.3324
0.3279
0.2789
0.3658
0.3425
0.2580
Median
0.137
0.180
0.238
0.309
0.372
0.406
Min.
-0.23
-0.15
-0.12
-0.06
-0.10
-0.06
Max.
1.72
1.49
1.43
2.05
2.12
1.51
Day 28
87
0.268
0.3722
0.191
-0.47
1.79
85
0.348
0.3480
0.241
-0.27
1.52
91
0.342
0.3328
0.295
-0.24
1.68
88
0.373
0.3339
0.327
-0.19
1.65
93
0.440
0.3106
0.437
-0.17
1.77
98
0.442
0.3420
0.370
-0.28
1.57
CONFIDENTIAL
342
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.29
Statistical Analysis of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
102
101
101
100
101
101
0.230(0.029)
0.309(0.029)
0.291(0.029)
0.385(0.029)
0.439(0.029)
0.459(0.029)
0.079
0.061
0.155
(-0.003,0.161) (-0.020,0.142) (0.073,0.236)
0.059
0.142
<0.001
0.209
(0.128,0.290)
<0.001
0.228
(0.146,0.310)
<0.001
343
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
87
0.253(0.034)
85
0.366(0.034)
0.113
(0.019,0.208)
0.019
91
0.333(0.033)
88
0.390(0.033)
0.079
0.137
(-0.013,0.172) (0.044,0.230)
0.091
0.004
93
0.430(0.032)
0.176
(0.085,0.268)
<0.001
98
0.442(0.032)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
0.189
(0.098,0.280)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.30
Summary of Weighted Mean Change from Baseline in FEV1 (L) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
100
101
Mean
0.108
0.184
0.178
0.265
0.325
0.331
SD
0.3190
0.3078
0.2605
0.3229
0.3131
0.2161
Median
0.023
0.089
0.148
0.200
0.270
0.294
Min.
-0.40
-0.23
-0.23
-0.15
-0.20
-0.21
Max.
1.58
1.32
1.33
1.87
1.95
0.97
Day 28
87
0.152
0.3659
0.104
-0.72
1.67
83
0.264
0.3364
0.164
-0.37
1.47
91
0.254
0.3326
0.183
-0.28
1.58
88
0.278
0.3205
0.235
-0.25
1.60
93
0.352
0.2989
0.314
-0.25
1.54
98
0.348
0.3283
0.286
-0.24
1.50
CONFIDENTIAL
344
n
Mean
SD
Median
Min.
Max.
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.31
Statistical Analysis of Weighted Mean Change from Baseline in FEV1 (L) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)
101
101
101
0.095(0.027)
0.202(0.027)
0.176(0.027)
0.107
(0.031,0.183)
0.006
0.081
(0.005,0.156)
0.037
0.173
(0.097,0.249)
<0.001
0.226
(0.151,0.302)
<0.001
0.236
(0.160,0.312)
<0.001
345
Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value
87
0.136(0.033)
83
0.281(0.034)
0.145
(0.051,0.238)
0.003
91
0.246(0.032)
0.110
(0.019,0.201)
0.018
88
0.296(0.033)
0.160
(0.068,0.252)
<0.001
93
0.341(0.032)
0.205
(0.115,0.295)
<0.001
98
0.349(0.031)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
99
100
101
0.268(0.027)
0.321(0.027)
0.331(0.027)
0.213
(0.123,0.302)
<0.001
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.32
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (0-4hrs)
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
23 / 99 (23%) 20 / 97 (21%) 25 / 100 (25%) 25 / 99 (25%) 45 / 98 (46%) 49 / 97 (51%)
1 hour
21 / 101 (21%) 24 / 101 (24%) 27 / 101 (27%) 33 / 99 (33%) 51 / 101 (50%) 62 / 101 (61%)
2 hours
24 / 100 (24%) 23 / 101 (23%) 32 / 101 (32%) 37 / 98 (38%) 56 / 101 (55%) 60 / 100 (60%)
3 hours
25 / 101 (25%) 26 / 100 (26%) 33 / 99 (33%) 42 / 99 (42%) 58 / 98 (59%) 58 / 100 (58%)
4 hours
22 / 100 (22%) 22 / 101 (22%) 28 / 101 (28%) 45 / 99 (45%) 58 / 100 (58%) 58 / 99 (59%)
346
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
30
27
23
25
26
28
24
/
/
/
/
/
/
/
89
86
85
87
87
86
86
(34%)
(31%)
(27%)
(29%)
(30%)
(33%)
(28%)
26
26
31
32
33
32
29
/
/
/
/
/
/
/
86
84
85
85
84
82
84
(30%)
(31%)
(36%)
(38%)
(39%)
(39%)
(35%)
32
30
32
35
34
37
33
/
/
/
/
/
/
/
91
90
90
91
91
91
91
(35%)
(33%)
(36%)
(38%)
(37%)
(41%)
(36%)
29
32
36
36
36
40
37
/
/
/
/
/
/
/
89
87
88
88
88
88
88
(33%)
(37%)
(41%)
(41%)
(41%)
(45%)
(42%)
43
46
54
53
53
55
55
/
/
/
/
/
/
/
94
93
93
93
93
92
93
(46%)
(49%)
(58%)
(57%)
(57%)
(60%)
(59%)
45
48
51
60
55
54
51
/
/
/
/
/
/
/
98
94
97
97
97
98
98
(46%)
(51%)
(53%)
(62%)
(57%)
(55%)
(52%)
CONFIDENTIAL
Day 28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.33
Summary of the Cumulative Proportion of Subjects Obtaining >=200mL and >=12% increase from
Baseline FEV1 (L) (0-4hrs)
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
24 / 102 (24%) 21 / 98 (21%) 25 / 101 (25%) 28 / 100 (28%) 48 / 100 (48%) 52 / 100 (52%)
1 hour
25 / 102 (25%) 27 / 101 (27%) 31 / 101 (31%) 38 / 100 (38%) 56 / 101 (55%) 69 / 101 (68%)
2 hours
29 / 102 (28%) 29 / 101 (29%) 37 / 101 (37%) 48 / 100 (48%) 61 / 101 (60%) 72 / 101 (71%)
3 hours
32 / 102 (31%) 32 / 101 (32%) 43 / 101 (43%) 54 / 100 (54%) 66 / 101 (65%) 76 / 101 (75%)
4 hours
35 / 102 (34%) 33 / 101 (33%) 45 / 101 (45%) 60 / 100 (60%) 70 / 101 (69%) 77 / 101 (76%)
347
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
30
30
30
33
34
36
37
/
/
/
/
/
/
/
89
89
89
89
89
89
89
(34%)
(34%)
(34%)
(37%)
(38%)
(40%)
(42%)
26
30
35
37
40
42
45
/
/
/
/
/
/
/
86
86
87
87
87
87
87
(30%)
(35%)
(40%)
(43%)
(46%)
(48%)
(52%)
32
33
35
39
40
43
44
/
/
/
/
/
/
/
91
91
91
91
91
91
91
(35%)
(36%)
(38%)
(43%)
(44%)
(47%)
(48%)
29
39
43
44
46
48
50
/
/
/
/
/
/
/
89
89
89
89
89
89
89
(33%)
(44%)
(48%)
(49%)
(52%)
(54%)
(56%)
43
48
57
61
62
65
65
/
/
/
/
/
/
/
94
94
94
94
94
94
94
(46%)
(51%)
(61%)
(65%)
(66%)
(69%)
(69%)
45
51
54
62
63
64
64
/
/
/
/
/
/
/
98
98
98
98
98
98
98
(46%)
(52%)
(55%)
(63%)
(64%)
(65%)
(65%)
CONFIDENTIAL
Day 28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.34
Summary of the Proportion of Subjects Obtaining >= 15% Increase from Baseline FEV1 (L) (0-4hrs)
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
12 / 102 (12%) 11 / 97 (11%) 12 / 99 (12%) 14 / 99 (14%) 32 / 98 (33%) 28 / 98 (29%)
30 mins
17 / 99 (17%) 15 / 97 (15%) 17 / 100 (17%) 16 / 99 (16%) 40 / 98 (41%) 39 / 97 (40%)
1 hour
18 / 101 (18%) 20 / 101 (20%) 19 / 101 (19%) 23 / 99 (23%) 43 / 101 (43%) 46 / 101 (46%)
2 hours
20 / 100 (20%) 21 / 101 (21%) 23 / 101 (23%) 27 / 98 (28%) 46 / 101 (46%) 50 / 100 (50%)
3 hours
19 / 101 (19%) 23 / 100 (23%) 22 / 99 (22%) 30 / 99 (30%) 52 / 98 (53%) 51 / 100 (51%)
4 hours
21 / 100 (21%) 18 / 101 (18%) 24 / 101 (24%) 31 / 99 (31%) 50 / 100 (50%) 53 / 99 (54%)
348
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
26
23
21
22
23
23
19
/
/
/
/
/
/
/
89
86
85
87
87
86
86
(29%)
(27%)
(25%)
(25%)
(26%)
(27%)
(22%)
23
22
24
28
29
28
22
/
/
/
/
/
/
/
86
84
85
85
84
82
84
(27%)
(26%)
(28%)
(33%)
(35%)
(34%)
(26%)
24
26
28
30
30
33
30
/
/
/
/
/
/
/
91
90
90
91
91
91
91
(26%)
(29%)
(31%)
(33%)
(33%)
(36%)
(33%)
18
26
29
29
29
31
33
/
/
/
/
/
/
/
89
87
88
88
88
88
88
(20%)
(30%)
(33%)
(33%)
(33%)
(35%)
(38%)
36
39
46
47
44
51
50
/
/
/
/
/
/
/
94
93
93
93
93
92
93
(38%)
(42%)
(49%)
(51%)
(47%)
(55%)
(54%)
36
44
45
50
46
49
45
/
/
/
/
/
/
/
98
94
97
97
97
98
98
(37%)
(47%)
(46%)
(52%)
(47%)
(50%)
(46%)
CONFIDENTIAL
Day 28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.35
Summary of the Cumulative Proportion of Subjects Obtaining
Baseline FEV1 (L) (0-4hrs)
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
12 / 102 (12%) 11 / 97 (11%) 12 / 99 (12%) 14 / 99 (14%) 32 / 98 (33%) 28 / 98 (29%)
30 mins
19 / 102 (19%) 15 / 98 (15%) 18 / 101 (18%) 18 / 100 (18%) 41 / 100 (41%) 42 / 100 (42%)
1 hour
21 / 102 (21%) 21 / 101 (21%) 22 / 101 (22%) 26 / 100 (26%) 48 / 101 (48%) 51 / 101 (50%)
2 hours
23 / 102 (23%) 25 / 101 (25%) 26 / 101 (26%) 33 / 100 (33%) 54 / 101 (53%) 57 / 101 (56%)
3 hours
24 / 102 (24%) 29 / 101 (29%) 30 / 101 (30%) 38 / 100 (38%) 60 / 101 (59%) 61 / 101 (60%)
4 hours
28 / 102 (27%) 29 / 101 (29%) 33 / 101 (33%) 43 / 100 (43%) 63 / 101 (62%) 64 / 101 (63%)
349
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
26
27
27
29
30
30
30
/
/
/
/
/
/
/
89
89
89
89
89
89
89
(29%)
(30%)
(30%)
(33%)
(34%)
(34%)
(34%)
23
25
27
31
34
35
35
/
/
/
/
/
/
/
86
86
87
87
87
87
87
(27%)
(29%)
(31%)
(36%)
(39%)
(40%)
(40%)
24
27
28
31
33
35
36
/
/
/
/
/
/
/
91
91
91
91
91
91
91
(26%)
(30%)
(31%)
(34%)
(36%)
(38%)
(40%)
18
28
35
35
38
41
42
/
/
/
/
/
/
/
89
89
89
89
89
89
89
(20%)
(31%)
(39%)
(39%)
(43%)
(46%)
(47%)
36
41
49
51
53
58
59
/
/
/
/
/
/
/
94
94
94
94
94
94
94
(38%)
(44%)
(52%)
(54%)
(56%)
(62%)
(63%)
36
48
52
56
57
57
57
/
/
/
/
/
/
/
98
98
98
98
98
98
98
(37%)
(49%)
(53%)
(57%)
(58%)
(58%)
(58%)
CONFIDENTIAL
Day 28
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.36
Summary of Peak Post-Dose FEV1 (L) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
86
85
91
88
93
97
Mean
2.458
2.739
2.709
2.660
2.591
2.660
SD
0.7916
0.8562
0.7743
0.8045
0.7088
0.6808
Median
2.410
2.591
2.672
2.537
2.456
2.679
Min.
1.03
1.36
1.31
1.16
1.24
1.48
Max.
4.74
5.06
4.41
5.10
4.15
5.03
CONFIDENTIAL
350
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.37
Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
86
85
91
88
93
97
LS Mean (SE)
2.517(0.034)
2.629(0.034)
2.596(0.032)
2.655(0.033)
2.694(0.032)
2.715(0.032)
Column vs Placebo
Difference
95% C.I.
p-value
0.112
(0.018,0.206)
0.020
0.079
0.138
(-0.013,0.171) (0.045,0.231)
0.093
0.004
0.177
(0.085,0.268)
<0.001
0.198
(0.107,0.289)
<0.001
CONFIDENTIAL
351
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.38
Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Ratio
n
86
84
91
88
93
96
Mean
1.042
1.045
1.040
1.043
1.056
1.060
SD
0.0912
0.0682
0.0533
0.0843
0.0718
0.0607
Median
1.031
1.036
1.028
1.032
1.048
1.050
Min.
0.78
0.81
0.97
0.63
0.92
0.96
Max.
1.36
1.35
1.25
1.32
1.34
1.24
CONFIDENTIAL
352
YM2008/00019/00
B2C109575
Note: Trough FEV1 as used in the ratio is the mean of the FEV1 values obtained 23 and 24 hours after dosing
on Day 28 (i.e., no imputation was used)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Baseline
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
102
101
101
100
101
102
Mean
362.3
393.4
400.2
382.7
375.8
355.0
SD
114.30
135.27
113.55
116.33
117.76
106.58
Median
342.7
396.6
387.8
373.5
362.5
341.5
Min.
102
100
168
105
76
148
Max.
638
681
695
636
681
656
CONFIDENTIAL
353
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
365.5
409.2
425.7
413.3
409.7
396.8
SD
113.20
136.33
115.03
117.64
120.26
112.86
Median
343.3
405.3
408.0
399.1
395.8
391.8
Min.
141
105
180
175
103
185
Max.
646
680
748
682
709
725
354
n
Mean
SD
Median
Min.
Max.
99
4.4
36.51
5.9
-109
193
99
16.4
36.56
15.4
-85
121
101
25.5
34.87
18.3
-43
127
98
30.7
34.68
29.0
-54
152
101
33.9
36.34
28.0
-47
187
102
41.8
38.17
38.6
-38
196
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 2
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
93
92
97
95
97
98
Mean
365.2
418.8
424.3
413.9
407.7
400.5
SD
110.07
124.84
117.97
115.87
120.47
112.08
Median
339.7
414.7
407.8
398.9
385.5
391.0
Min.
150
134
183
154
117
191
Max.
619
669
719
700
718
707
355
n
Mean
SD
Median
Min.
Max.
93
4.1
38.88
5.1
-153
162
92
13.4
42.85
10.8
-71
175
97
22.6
37.05
17.0
-56
132
95
30.1
44.20
20.4
-47
159
97
32.1
39.43
27.7
-57
206
98
40.6
47.27
29.4
-44
245
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 3
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
90
85
91
92
94
97
Mean
363.6
428.4
432.7
411.8
409.0
398.0
SD
113.75
123.66
115.33
112.96
120.28
114.21
Median
339.8
424.6
403.1
399.3
391.8
383.4
Min.
142
119
191
155
128
191
Max.
657
685
712
671
705
704
356
n
Mean
SD
Median
Min.
Max.
90
3.2
39.31
-2.1
-95
199
85
15.2
43.26
6.9
-61
197
91
24.4
38.52
17.6
-43
151
92
28.3
49.91
19.1
-57
204
94
35.3
43.86
27.4
-52
266
97
38.9
47.44
31.0
-43
242
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 4
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
85
84
88
89
93
98
Mean
366.7
419.6
428.7
413.3
406.5
397.7
SD
111.54
127.31
116.29
108.67
119.39
116.91
Median
348.0
408.8
405.7
402.1
396.7
382.5
Min.
131
110
177
171
135
184
Max.
593
676
701
696
695
722
357
n
Mean
SD
Median
Min.
Max.
85
5.6
41.32
3.6
-66
201
84
11.3
46.48
4.9
-77
185
88
22.0
42.67
21.0
-98
164
89
29.1
48.89
20.2
-67
187
93
35.2
44.41
30.6
-66
249
98
38.2
52.76
30.9
-50
263
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
364.7
406.7
423.7
412.1
408.9
396.6
SD
111.57
134.34
115.53
116.02
118.87
112.60
Median
343.6
408.1
405.3
397.6
390.5
393.2
Min.
146
106
182
164
110
185
Max.
634
674
725
680
714
715
358
n
Mean
SD
Median
Min.
Max.
99
3.6
36.09
5.1
-119
177
99
13.9
37.86
11.5
-85
123
101
23.6
34.13
21.6
-45
129
98
29.4
38.04
22.2
-54
135
101
33.2
36.38
28.2
-52
197
102
41.7
41.38
34.1
-41
223
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
363.2
404.9
422.9
411.6
409.2
395.8
SD
111.05
134.26
114.74
113.62
117.05
113.69
Median
339.5
405.3
405.9
401.6
390.7
385.7
Min.
146
106
183
163
124
185
Max.
623
678
718
677
707
713
359
n
Mean
SD
Median
Min.
Max.
99
2.1
37.13
2.4
-119
188
99
12.0
38.22
8.6
-85
158
101
22.8
34.82
19.2
-59
138
98
29.0
41.85
20.4
-54
149
101
33.4
38.28
29.0
-42
222
102
40.8
44.16
33.9
-32
225
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Endpoint
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
98
99
101
98
101
102
Mean
360.9
400.5
421.3
412.9
408.0
392.9
SD
109.99
135.97
116.52
110.92
117.49
117.74
Median
339.9
399.4
401.0
404.1
392.1
377.5
Min.
131
103
177
171
135
184
Max.
583
673
723
696
696
722
360
n
Mean
SD
Median
Min.
Max.
98
0.3
44.08
1.3
-154
201
99
7.6
43.46
5.0
-85
185
101
21.2
41.22
16.4
-98
161
98
30.3
51.48
21.1
-68
204
101
32.2
46.20
27.4
-66
273
102
37.9
52.57
30.5
-52
263
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Follow-up
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
64
78
69
80
78
83
Mean
372.4
424.2
419.1
409.0
385.8
392.0
SD
110.94
119.16
114.15
115.41
121.46
119.66
Median
346.7
413.2
387.0
388.0
373.4
380.3
Min.
149
161
171
173
126
192
Max.
625
674
731
758
708
690
361
n
Mean
SD
Median
Min.
Max.
64
14.5
52.26
9.8
-90
221
78
8.2
48.78
5.6
-96
167
69
18.1
42.04
21.6
-88
104
80
24.7
53.83
16.5
-69
209
78
19.1
42.38
15.5
-82
186
83
29.8
56.27
22.4
-72
236
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.40
Statistical Analysis of Change from Baseline in PM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean
378.3
391.9
402.4
406.7
411.8
416.2
LS Mean Change (SE)
0.4 (3.87)
14.0 (3.87)
24.5 (3.82)
28.9 (3.87)
34.0 (3.81)
38.4 (3.82)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
13.6
(2.8, 24.4)
0.014
24.1
(13.5, 34.8)
<0.001
28.5
(17.7, 39.3)
<0.001
33.6
(22.9, 44.2)
<0.001
38.0
(27.3, 48.7)
<0.001
CONFIDENTIAL
362
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Baseline
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
102
101
101
100
101
102
Mean
345.6
377.4
387.5
366.3
360.7
340.1
SD
113.65
128.51
114.40
113.51
116.68
107.46
Median 330.1
371.8
379.9
355.4
353.2
321.5
Min.
104
106
158
105
88
131
Max.
617
691
659
625
638
662
CONFIDENTIAL
363
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
97
101
101
Mean
349.5
393.7
414.3
400.9
397.0
384.8
SD
113.10
128.07
115.92
117.11
119.35
110.44
Median 332.4
395.5
401.7
385.7
389.0
372.3
Min.
111
91
170
163
101
188
Max.
647
685
685
658
659
681
364
n
Mean
SD
Median
Min.
Max.
98
4.5
31.84
1.6
-58
141
99
16.7
36.90
15.1
-105
108
101
26.7
29.62
24.5
-38
120
97
34.4
35.94
34.6
-65
146
101
36.2
36.28
34.7
-79
168
101
47.1
35.10
44.5
-40
174
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 2
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
93
93
97
94
97
98
Mean
346.5
404.1
412.6
403.5
397.9
390.6
SD
111.68
120.83
119.46
117.26
120.17
111.82
Median 323.9
401.0
399.1
394.0
377.0
381.7
Min.
122
146
175
157
104
165
Max.
664
677
698
659
686
687
365
n
Mean
SD
Median
Min.
Max.
93
2.4
37.16
2.7
-76
155
93
17.4
44.01
13.6
-97
209
97
23.0
34.57
18.3
-81
124
94
35.8
42.28
31.9
-75
144
97
35.9
41.05
32.4
-78
206
98
46.1
43.51
43.0
-71
192
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 3
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
90
86
91
92
94
98
Mean
349.7
415.2
421.4
403.0
400.0
390.9
SD
113.11
119.80
115.96
113.57
118.80
116.57
Median 325.8
413.9
405.4
395.8
378.4
375.0
Min.
123
152
169
167
129
175
Max.
630
689
684
673
689
677
366
n
Mean
SD
Median
Min.
Max.
90
5.3
40.40
0.9
-76
175
86
22.7
45.38
12.4
-77
230
91
25.3
36.58
19.3
-45
133
92
35.8
48.89
27.0
-53
232
94
40.0
40.79
36.6
-48
224
98
46.8
46.88
44.4
-62
184
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 4
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
87
84
90
89
93
98
Mean
348.0
408.9
420.2
401.0
399.5
389.3
SD
108.67
122.65
117.28
109.80
119.59
115.28
Median 338.1
393.7
399.1
382.8
388.8
377.2
Min.
121
101
170
154
120
164
Max.
624
670
673
672
703
665
367
n
Mean
SD
Median
Min.
Max.
87
3.2
42.02
0.6
-95
191
84
18.8
48.62
13.6
-76
211
90
23.0
35.60
13.0
-39
120
89
33.5
45.83
30.5
-106
193
93
41.7
47.25
38.0
-52
297
98
45.2
45.94
40.1
-39
186
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
348.8
393.4
412.5
400.6
396.9
386.9
SD
112.00
126.91
116.41
115.58
118.47
111.64
Median 327.0
393.0
401.7
389.0
384.9
381.1
Min.
117
88
173
164
111
185
Max.
656
681
683
656
672
685
368
n
Mean
SD
Median
Min.
Max.
98
3.8
32.61
1.0
-50
149
99
16.4
38.05
12.6
-101
138
101
24.9
30.30
17.7
-34
117
98
34.3
37.20
32.6
-65
133
101
36.2
36.93
32.4
-76
189
102
46.8
36.42
44.8
-55
157
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
348.7
393.6
412.3
400.7
398.5
386.5
SD
110.82
127.00
115.43
114.11
116.54
112.92
Median 328.1
390.0
401.5
391.9
376.9
378.0
Min.
120
88
171
163
126
177
Max.
641
680
678
657
682
672
369
n
Mean
SD
Median
Min.
Max.
98
3.7
34.81
-0.2
-58
167
99
16.5
39.57
9.0
-89
172
101
24.7
31.68
19.3
-34
120
98
34.5
41.31
28.7
-65
149
101
37.8
38.19
34.7
-76
217
102
46.4
39.07
42.7
-53
171
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Endpoint
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
345.9
392.8
411.9
401.6
399.6
384.9
SD
108.15
128.77
116.70
113.47
116.90
114.75
Median 333.6
390.3
393.2
382.9
396.4
378.9
Min.
121
88
170
154
120
164
Max.
624
675
676
673
696
665
370
n
Mean
SD
Median
Min.
Max.
98
0.8
40.83
0.6
-77
191
99
15.8
46.68
10.5
-76
211
101
24.4
37.66
12.7
-34
119
98
35.3
52.84
30.9
-127
232
101
38.9
46.05
36.5
-73
268
102
44.8
45.66
40.0
-43
191
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Follow-up
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
65
79
71
81
78
84
Mean
346.7
405.1
403.9
395.9
377.5
380.1
SD
106.80
115.11
111.21
110.68
115.81
116.66
Median 321.3
397.0
385.2
385.8
373.9
360.7
Min.
113
161
161
135
103
185
Max.
583
660
662
651
678
662
371
n
Mean
SD
Median
Min.
Max.
65
13.0
42.76
9.0
-82
151
79
9.7
46.53
6.4
-89
182
71
15.7
43.19
15.0
-115
141
81
30.6
46.67
28.4
-66
197
78
26.8
37.67
26.3
-54
155
84
34.6
49.25
28.2
-102
187
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.42
Statistical Analysis of Change from Baseline in AM PEF (L/min)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean
364.7
381.4
389.5
397.0
400.9
406.7
LS Mean Change (SE)
1.9 (3.69)
18.7 (3.67)
26.8 (3.63)
34.2 (3.68)
38.1 (3.61)
44.0 (3.63)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
16.8
(6.5, 27.1)
0.001
24.9
(14.7, 35.1)
<0.001
32.3
(22.1, 42.6)
<0.001
36.2
(26.1, 46.4)
<0.001
42.1
(31.9, 52.2)
<0.001
CONFIDENTIAL
372
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.43
Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
10.2
10.5
10.8
10.5
11.6
8.5
SD
18.29
20.21
22.55
21.64
21.36
16.13
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
71
n
Mean
SD
Median
Min.
Max.
98
24.6
28.79
11.6
0
100
99
31.9
33.67
19.0
0
100
101
33.3
35.15
22.2
0
100
98
38.6
37.37
34.5
0
100
101
48.2
38.87
50.0
0
100
102
41.6
37.23
34.1
0
100
n
Mean
SD
Median
Min.
Max.
98
14.6
25.97
3.8
-35
93
99
21.4
31.27
7.4
-31
100
101
22.5
31.71
11.7
-71
100
98
27.8
35.21
16.5
-43
100
101
36.5
36.33
33.3
-21
100
102
33.1
34.72
27.2
-40
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
373
Symptom Free
24 Hour Periods (%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.44
Statistical Analysis of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 14.2 (3.27)
22.6 (3.25)
23.6 (3.21)
26.8 (3.26)
36.4 (3.21)
32.3 (3.21)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
8.4
(-0.7, 17.5)
0.069
9.4
(0.4, 18.4)
0.040
12.7
(3.6, 21.8)
0.006
22.2
(13.3, 31.2)
<0.001
18.1
(9.1, 27.2)
<0.001
CONFIDENTIAL
374
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.45
Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
14.8
15.3
12.1
10.4
12.7
13.3
SD
24.77
25.76
22.04
21.63
21.11
23.28
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.
99
29.2
31.43
18.5
0
100
99
38.7
37.51
34.6
0
100
101
38.9
36.45
30.4
0
100
98
42.7
39.42
35.7
0
100
101
56.5
36.07
69.2
0
100
102
47.4
38.30
51.9
0
100
n
Mean
SD
Median
Min.
Max.
99
15.3
27.69
3.8
-43
96
99
23.1
35.07
7.4
-56
100
101
26.7
32.13
15.4
-29
100
98
32.1
36.18
22.6
-43
100
101
43.7
37.16
45.8
-32
100
102
34.1
36.43
30.7
-48
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
375
Rescue Free
24 Hour Periods (%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.46
Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.0 (3.33) 25.8 (3.33)
27.3 (3.28)
29.6 (3.34)
43.4 (3.28)
34.0 (3.28)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
10.8
(1.5, 20.1)
0.023
12.3
(3.1, 21.5)
0.009
14.7
(5.4, 24.0)
0.002
28.4
(19.3, 37.6)
<0.001
19.0
(9.8, 28.3)
<0.001
CONFIDENTIAL
376
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.47
Change from Baseline in Percentage of Symptom Free Days
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
16.3
16.5
15.9
16.8
19.5
14.9
SD
22.45
25.56
26.77
26.07
26.09
22.57
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.
99
32.5
32.40
19.2
0
100
99
38.1
35.40
30.8
0
100
101
42.3
36.82
35.7
0
100
98
44.9
38.17
43.2
0
100
101
55.1
38.83
65.0
0
100
102
50.3
37.48
55.6
0
100
n
Mean
SD
Median
Min.
Max.
99
16.0
28.60
4.2
-38
96
99
21.5
32.33
10.7
-46
100
101
26.4
33.58
17.9
-64
100
98
27.9
33.72
21.2
-43
100
101
35.6
34.30
29.6
-14
100
102
35.4
34.62
29.4
-29
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
377
Days 1-28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.48
Statistical Analysis of Change from Baseline in Percentage of Symptom Free Days
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.8 (3.24)
22.5 (3.24)
26.9 (3.20)
27.1 (3.25)
36.1 (3.20)
34.4 (3.19)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
6.7
(-2.3, 15.8)
0.146
11.1
(2.2, 20.0)
0.015
11.4
(2.3, 20.4)
0.014
20.3
(11.4, 29.2)
<0.001
18.6
(9.6, 27.6)
<0.001
CONFIDENTIAL
378
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.49
Change from Baseline in Percentage of Symptom Free Nights
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
42.5
35.9
40.9
40.5
40.6
34.0
SD
39.35
37.02
38.75
42.21
37.58
36.96
Median
31.0
28.6
33.3
16.7
40.0
15.5
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.
98
53.8
36.49
59.0
0
100
99
54.2
38.28
65.4
0
100
101
59.0
39.50
71.4
0
100
98
64.2
38.78
83.6
0
100
101
70.7
35.51
89.3
0
100
102
59.4
38.45
68.5
0
100
n
Mean
SD
Median
Min.
Max.
98
12.7
27.58
0.0
-43
100
99
18.6
36.33
6.4
-100
100
101
18.1
33.04
4.8
-96
96
98
22.9
34.63
4.3
-53
100
101
30.1
35.89
24.7
-43
100
102
25.4
33.81
17.3
-39
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
379
Days 1-28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.50
Statistical Analysis of Change from Baseline in Percentage of Symptom Free Nights
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 13.2 (3.04)
18.2 (3.02)
19.7 (2.98)
23.1 (3.03)
30.3 (2.98)
23.2 (2.98)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
5.0
(-3.5, 13.4)
0.249
6.5
(-1.9, 14.8)
0.128
9.9
(1.4, 18.3)
0.022
17.1
(8.8, 25.4)
<0.001
10.0
(1.6, 18.4)
0.020
CONFIDENTIAL
380
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.51
Change from Baseline in Percentage of Rescue Free Days
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
22.0
23.5
19.5
19.0
22.7
21.2
SD
27.73
30.37
26.10
27.85
27.52
26.64
Median
14.3
14.3
14.3
14.3
14.3
14.3
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.
99
37.2
33.52
33.3
0
100
99
44.7
38.20
40.0
0
100
101
49.2
36.78
48.0
0
100
98
47.8
39.69
41.0
0
100
101
63.1
35.08
75.0
0
100
102
56.0
37.09
69.1
0
100
n
Mean
SD
Median
Min.
Max.
99
15.9
29.02
4.8
-39
100
99
20.7
35.49
6.9
-50
100
101
29.8
34.46
21.1
-43
100
98
28.5
36.03
17.2
-52
100
101
40.4
36.83
40.0
-47
100
102
34.8
35.84
26.8
-50
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
381
Days 1-28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.52
Statistical Analysis of Change from Baseline in Percentage of Rescue Free Days
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.3 (3.29)
23.4 (3.29)
29.6 (3.25)
26.2 (3.30)
41.0 (3.24)
34.5 (3.24)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
8.0
(-1.2, 17.2)
0.087
14.2
(5.2, 23.3)
0.002
10.9
(1.7, 20.0)
0.020
25.6
(16.6, 34.7)
<0.001
19.2
(10.1, 28.3)
<0.001
CONFIDENTIAL
382
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.53
Change from Baseline in Percentage of Rescue Free Nights
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
45.5
39.6
38.6
36.9
38.2
36.8
SD
39.14
38.89
37.66
41.37
35.34
37.74
Median
42.9
28.6
28.6
14.3
33.3
28.6
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.
98
54.7
36.62
63.0
0
100
99
57.7
38.71
67.9
0
100
101
60.7
37.10
71.4
0
100
98
63.3
39.10
84.9
0
100
101
75.5
32.54
92.0
0
100
102
65.5
36.65
84.8
0
100
n
Mean
SD
Median
Min.
Max.
98
10.6
31.49
3.8
-92
100
99
18.3
36.84
10.3
-100
100
101
22.1
34.93
10.7
-68
100
98
25.6
33.22
7.7
-44
96
101
37.2
35.85
32.1
-37
100
102
28.7
35.15
22.3
-40
100
YM2008/00019/00
B2C109575
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
CONFIDENTIAL
383
Days 1-28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.54
Statistical Analysis of Change from Baseline in Percentage of Rescue Free Nights
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 12.6 (3.05)
19.2 (3.03)
22.6 (2.99)
24.0 (3.04)
36.7 (2.98)
27.5 (2.98)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value
6.7
(-1.8, 15.1)
0.123
10.0
(1.6, 18.4)
0.020
11.4
(3.0, 19.9)
0.008
24.1
(15.7, 32.5)
<0.001
14.9
(6.5, 23.3)
<0.001
CONFIDENTIAL
384
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.55
Statistical Analysis of Withdrawals Due to Lack of Efficacy
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------No. of subjects whose primary
9
(9%)
12 (12%)
3
(3%)
5
(5%)
4
(4%)
0
reason for withdrawal was lack
of efficacy
Column vs Placebo
p-value
0.499
0.134
0.407
0.251
0.003
CONFIDENTIAL
385
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.105
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (0-24hrs)
Day 28
30
27
23
25
26
28
24
15
15
30
33
29
27
26
/
/
/
/
/
/
/
/
/
/
/
/
/
/
89
86
85
87
87
86
86
59
59
87
87
87
86
86
(34%)
(31%)
(27%)
(29%)
(30%)
(33%)
(28%)
(25%)
(25%)
(34%)
(38%)
(33%)
(31%)
(30%)
26
26
31
32
33
32
29
24
21
39
31
36
28
26
/
/
/
/
/
/
/
/
/
/
/
/
/
/
86
84
85
85
84
82
84
56
56
84
84
84
84
83
(30%)
(31%)
(36%)
(38%)
(39%)
(39%)
(35%)
(43%)
(38%)
(46%)
(37%)
(43%)
(33%)
(31%)
32
30
32
35
34
37
33
25
22
35
38
36
33
35
/
/
/
/
/
/
/
/
/
/
/
/
/
/
91
90
90
91
91
91
91
61
61
90
91
90
90
91
(35%)
(33%)
(36%)
(38%)
(37%)
(41%)
(36%)
(41%)
(36%)
(39%)
(42%)
(40%)
(37%)
(38%)
29
32
36
36
36
40
37
25
21
35
39
31
35
33
/
/
/
/
/
/
/
/
/
/
/
/
/
/
89
87
88
88
88
88
88
64
64
88
87
85
87
87
(33%)
(37%)
(41%)
(41%)
(41%)
(45%)
(42%)
(39%)
(33%)
(40%)
(45%)
(36%)
(40%)
(38%)
43
46
54
53
53
55
55
40
33
53
59
53
52
54
/
/
/
/
/
/
/
/
/
/
/
/
/
/
94
93
93
93
93
92
93
56
56
93
93
93
93
93
(46%)
(49%)
(58%)
(57%)
(57%)
(60%)
(59%)
(71%)
(59%)
(57%)
(63%)
(57%)
(56%)
(58%)
45
48
51
60
55
54
51
31
27
51
53
48
48
50
/
/
/
/
/
/
/
/
/
/
/
/
/
/
98
94
97
97
97
98
98
57
58
97
97
94
97
96
(46%)
(51%)
(53%)
(62%)
(57%)
(55%)
(52%)
(54%)
(47%)
(53%)
(55%)
(51%)
(49%)
(52%)
YM2008/00019/00
B2C109575
Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours
CONFIDENTIAL
386
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
23 / 99 (23%) 20 / 97 (21%) 25 / 100 (25%) 25 / 99 (25%) 45 / 98 (46%) 49 / 97 (51%)
1 hour
21 / 101 (21%) 24 / 101 (24%) 27 / 101 (27%) 33 / 99 (33%) 51 / 101 (50%) 62 / 101 (61%)
2 hours
24 / 100 (24%) 23 / 101 (23%) 32 / 101 (32%) 37 / 98 (38%) 56 / 101 (55%) 60 / 100 (60%)
3 hours
25 / 101 (25%) 26 / 100 (26%) 33 / 99 (33%) 42 / 99 (42%) 58 / 98 (59%) 58 / 100 (58%)
4 hours
22 / 100 (22%) 22 / 101 (22%) 28 / 101 (28%) 45 / 99 (45%) 58 / 100 (58%) 58 / 99 (59%)
6 hours
17 / 66 (26%) 17 / 67 (25%) 30 / 69 (43%) 29 / 71 (41%) 39 / 62 (63%) 40 / 59 (68%)
12 hours 16 / 66 (24%) 20 / 66 (30%) 22 / 70 (31%) 23 / 70 (33%) 32 / 62 (52%) 37 / 60 (62%)
16 hours 31 / 101 (31%) 33 / 100 (33%) 42 / 101 (42%) 36 / 99 (36%) 58 / 101 (57%) 57 / 101 (56%)
20 hours 35 / 100 (35%) 39 / 99 (39%) 40 / 101 (40%) 32 / 99 (32%) 58 / 101 (57%) 56 / 99 (57%)
22 hours 31 / 101 (31%) 30 / 99 (30%) 36 / 101 (36%) 34 / 96 (35%) 52 / 100 (52%) 53 / 100 (53%)
23 hours 30 / 99 (30%) 35 / 101 (35%) 34 / 101 (34%) 33 / 98 (34%) 50 / 99 (51%) 51 / 100 (51%)
24 hours 28 / 98 (29%) 32 / 98 (33%) 34 / 101 (34%) 33 / 97 (34%) 48 / 98 (49%) 52 / 99 (53%)
CONFIDENTIAL
YM2008/00019/00
B2C109575
Figure 8.1 Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline
LFT Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.2 Box-Plot of Maximum Post Baseline Liver Function Tests . . . . . . . . . . . .
Figure 8.3 Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted
Mean Pulse Rate at Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.4 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc
(F) Interval (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.5 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc
(B) Interval (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.6 Mean (95% CI) Change From Baseline in QTc (F) interval by Time and
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.7 Mean (95% CI) Change From Baseline in QTc (B) interval by Time and
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.8 Adjusted Treatment Differences (95% CI) of Change from Baseline in
Post-Dose Serial QTc(F) (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.9 Adjusted Treatment Differences (95% CI) of Change from Baseline in
Post-Dose Serial QTc(B) (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.10 Serial QTc(F) (msec) versus Heart Rate (beats/min) . . . . . . . . . . . . . . .
Figure 8.11 Serial QTc(B) (msec) versus Heart Rate (beats/min) . . . . . . . . . . . . . . .
Figure 8.12 Minimum Post-Baseline Potassium Values Versus Baseline Potassium
Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.13 Box Plot of Minimum Post-Baseline Potassium Values . . . . . . . . . . . . .
Figure 8.14 Maximum Post-Baseline Glucose Values Versus Baseline Glucose
Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.15 Box Plot of Maximum Post-Baseline Glucose Values. . . . . . . . . . . . . . .
Figure 8.16 Mean Fasting Potassium by Time and Treatment . . . . . . . . . . . . . . . . .
Figure 8.17 Mean Fasting Glucose by Time and Treatment . . . . . . . . . . . . . . . . . . .
Figure 8.18 Box Plot of Maximum Increase from Baseline in Pulse Rate
(beats/min) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.101 Potassium Profiles for Subjects with Values >7 (MMOL/L). . . . . . . . . .
Table 8.1 Summary of Exposure (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . .
Table 8.2 Summary of On-Treatment Adverse Events (Intent-to-Treat Population) .
Table 8.3 Summary of Post-Treatment Adverse Events (Intent-to-Treat Population)
Table 8.4 Summary of Most Frequent On-Treatment Adverse Events
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.5 Summary of Drug-Related Adverse Events (Intent-to-Treat Population) . .
Table 8.6 Summary of Adverse Events Leading to Permanent Discontinuation of
Study drug or Withdrawal from the Study (Intent-to-Treat Population) . . . . . . .
387
392
393
394
395
399
403
407
411
415
419
439
459
460
461
462
463
464
465
466
475
476
483
485
486
489
CONFIDENTIAL
YM2008/00019/00
B2C109575
388
490
491
492
493
502
521
540
550
563
576
584
588
606
624
625
626
630
631
632
636
637
638
642
CONFIDENTIAL
YM2008/00019/00
B2C109575
Table 8.30 Summary of Weighted Mean Change from Pre-Dose in Systolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.31 Statistical Analysis of Weighted Mean Change from Baseline in
Systolic Blood Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . .
Table 8.32 Summary of Weighted Mean Change from Baseline in Diastolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.33 Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.34 Statistical Analysis of Weighted Mean Change from Baseline in
Diastolic Blood Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . .
Table 8.35 Summary of Weighted Mean Change from Baseline in Pulse Rate
(beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.36 Summary of Weighted Mean Change from Pre-Dose in Pulse Rate
(beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.37 Statistical Analysis of Weighted Mean Change from Baseline in Pulse
Rate (beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . .
Table 8.38 Summary of ECG Values (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 8.39 Summary of ECG Findings (Intent-to-Treat Population) . . . . . . . . . . . . .
Table 8.40 Summary of Maximum Post-Dose QTc(F) Interval (msec)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.41 Summary of Maximum Post-Dose QTc(B) Interval (msec)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.42 Summary of Maximum Change From Baseline (0-4 hours) in QTc(F)
Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.43 Summary of Maximum Change From Baseline (0-4 hours) in QTc(B)
Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.44 Summary of Weighted Mean Change From Baseline (0-4 hours) in
QTc(F) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.45 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in
QTc(F) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.46 Summary of Weighted Mean Change From Baseline (0-4 hours) in
QTc(B) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.47 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in
QTc(B) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.48 Statistical Analysis of Change from Baseline in Post-Dose Serial
QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.49 Statistical Analysis of Change from Baseline in Post-Dose Serial
QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.50 Statistical Analysis of Change from Baseline in Maximum Value (0-4
hrs) QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.51 Statistical Analysis of Change from Baseline in Maximum Value (0-4
hrs) QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
389
643
644
648
649
650
654
655
656
660
696
717
718
719
721
723
724
725
726
727
743
759
763
CONFIDENTIAL
YM2008/00019/00
B2C109575
Table 8.52 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs)
QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.53 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs)
QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.54 Summary of Fasting Potassium and Glucose (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.55 Summary of Non-Fasting Potassium (Intent-to-Treat Population) . . . . . .
Table 8.56 Summary of Fasting Potassium and Glucose Changes from Baseline
Relative to the Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . .
Table 8.57 Summary of Non-Fasting Potassium Changes from Baseline Relative
to the Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.58 Summary of Maximum Decrease from Baseline in Fasting Potassium
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.59 Summary of Maximum Decrease from Pre-Dose in Fasting Potassium
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.60 Summary of Maximum Decrease from Baseline in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.61 Summary of Maximum Decrease from Pre-Dose in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.62 Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.63 Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.64 Summary of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.65 Summary of Weighted Mean Change from Pre-Dose in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.66 Summary of Weighted Mean Change from Baseline in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.67 Summary of Weighted Mean Change from Pre-Dose in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.68 Summary of Weighted Mean Change from Baseline in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.69 Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.70 Statistical Analysis of Maximum Decrease from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.71 Statistical Analysis of Maximum Decrease from Baseline in
Non-Fasting Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.72 Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
390
767
771
775
781
784
790
793
794
795
796
797
798
799
800
801
802
803
804
805
807
809
CONFIDENTIAL
YM2008/00019/00
B2C109575
Table 8.73 Statistical Analysis of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.74 Statistical Analysis of Weighted Mean Change from Baseline in
Non-Fasting Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.75 Statistical Analysis of Weighted Mean Change from Baseline in
Glucose (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.76 Summary of Subjects with Asthma Exacerbations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
391
811
813
815
817
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.1
Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline LFT Values
ALT
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Alk. Phos.
Total Bili.
0.0
1.0
2.0
0.0
1.0
2.0
0.0
1.0
CONFIDENTIAL
392
Maximum (/ULN)
AST
2.0
0.0
1.0
2.0
Baseline (/ULN)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Clinical Concern Levels: AST, ALT, Alk Phos : 2xULN, Total Bili : 1.5xULN
Note: Shows each subjects maximum value against their baseline value, each divided by the upper limit of normal
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.2
Box-Plot of Maximum Post Baseline Liver Function Tests
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see
the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
393
YM2008/00019/00
B2C109575
Note: Graph includes subjects who were below ULN at baseline. Shows each subjects maximum value divided by the upper limit of normal
Clinical concern levels: AST, ALT, Alk. Phos: 2xULN, Total Bili: 1.5xULN
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.3
Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted Mean Pulse Rate at Day 28
0.4
0.3
CONFIDENTIAL
394
FEV1 (L) Change from Baseline Difference From Placebo and 95% CI
0.5
0.2
0.1
0.0
-6
-3
Pulse Rate (beats/min) Weighted Mean Change from Baseline (0-4 hrs) Difference From Placebo and 95% CI
Treatment
3mcg
6.25mcg
12.5mcg
Note: Analyses performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum, and treatment
25mcg
50mcg
YM2008/00019/00
B2C109575
-0.1
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 1
1.0
CONFIDENTIAL
395
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 7
1.0
CONFIDENTIAL
396
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 14
1.0
CONFIDENTIAL
397
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 28
1.0
CONFIDENTIAL
398
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 1
1.0
CONFIDENTIAL
399
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 7
1.0
CONFIDENTIAL
400
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 14
1.0
CONFIDENTIAL
401
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 28
1.0
CONFIDENTIAL
402
Cumulative Probability
0.8
0.6
0.4
0.0
-50
50
Change in QTc (msec)
Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)
100
YM2008/00019/00
B2C109575
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
0.2
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment
2 hours
4 hours
CONFIDENTIAL
403
Day: 1
-5
1 hour
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment
CONFIDENTIAL
404
Day: 7
-5
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment
CONFIDENTIAL
405
Day: 14
-5
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment
CONFIDENTIAL
406
Day: 28
-5
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 1
15
-5
2 hours
4 hours
CONFIDENTIAL
407
10
-10
1 hour
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 7
15
-5
CONFIDENTIAL
408
10
-10
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 14
15
CONFIDENTIAL
409
10
-5
-10
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 28
15
-5
CONFIDENTIAL
410
10
-10
1 hour
2 hours
4 hours
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Pre-dose 10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 1
10
-5
CONFIDENTIAL
411
QTc (msec)
-10
0
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 7
10
-5
CONFIDENTIAL
412
QTc (msec)
-10
0
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 14
10
-5
CONFIDENTIAL
413
QTc (msec)
-10
0
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 28
10
-5
CONFIDENTIAL
414
QTc (msec)
-10
0
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 1
15
-5
CONFIDENTIAL
415
QTc (msec)
10
-10
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 7
15
-5
CONFIDENTIAL
416
QTc (msec)
10
-10
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 14
15
-5
CONFIDENTIAL
417
QTc (msec)
10
-10
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 28
15
-5
CONFIDENTIAL
418
QTc (msec)
10
-10
3mcg
6.25mcg
50mcg
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
YM2008/00019/00
B2C109575
Time (hours)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, Pre-dose
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
419
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 10 mins
QTc(F) (msec)
420
400
350
60
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 1 hour
400
350
CONFIDENTIAL
421
QTc(F) (msec)
450
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 2 hours
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
QTc(F) (msec)
450
422
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 4 hours
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
423
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, Pre-dose
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
424
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 10 mins
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
425
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 1 hour
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
426
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 2 hours
450
400
350
CONFIDENTIAL
427
QTc(F) (msec)
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 4 hours
450
QTc(F) (msec)
400
350
CONFIDENTIAL
428
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, Pre-dose
450
400
350
CONFIDENTIAL
429
QTc(F) (msec)
40
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 10 mins
400
350
CONFIDENTIAL
430
QTc(F) (msec)
450
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 1 hour
400
350
CONFIDENTIAL
431
QTc(F) (msec)
450
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 2 hours
450
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
432
QTc(F) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
450
400
350
CONFIDENTIAL
433
QTc(F) (msec)
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, Pre-dose
400
350
60
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
434
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 10 mins
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
435
QTc(F) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 1 hour
450
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
436
QTc(F) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 2 hours
450
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
437
QTc(F) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 20 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 4 hours
400
350
CONFIDENTIAL
438
QTc(F) (msec)
450
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, Pre-dose
500
439
QTc(B) (msec)
450
400
350
CONFIDENTIAL
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 10 mins
500
440
QTc(B) (msec)
450
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 1 hour
500
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
441
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 2 hours
500
442
QTc(B) (msec)
450
400
350
CONFIDENTIAL
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 4 hours
500
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
443
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, Pre-dose
500
400
350
60
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Placebo
CONFIDENTIAL
444
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 10 mins
500
450
400
350
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
60
Heart Rate (beats/min)
Placebo
40
CONFIDENTIAL
445
QTc(B) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 1 hour
500
400
350
CONFIDENTIAL
446
QTc(B) (msec)
450
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 2 hours
500
450
447
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
QTc(B) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 4 hours
500
450
400
350
60
80
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
100
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
448
QTc(B) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, Pre-dose
500
400
350
60
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Placebo
CONFIDENTIAL
QTc(B) (msec)
450
449
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 10 mins
500
450
QTc(B) (msec)
450
400
350
CONFIDENTIAL
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 1 hour
500
450
400
350
3mcg
80
100
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
60
Heart Rate (beats/min)
Placebo
40
CONFIDENTIAL
451
QTc(B) (msec)
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 2 hours
500
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
452
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 4 hours
500
400
350
80
100
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
60
Heart Rate (beats/min)
Placebo
40
CONFIDENTIAL
453
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, Pre-dose
500
400
350
40
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
CONFIDENTIAL
454
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 10 mins
500
400
350
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
60
Heart Rate (beats/min)
40
CONFIDENTIAL
455
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 1 hour
500
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
456
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 2 hours
500
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
457
QTc(B) (msec)
450
Protocol: B2C109575
Population: Intent-to-Treat
Page 20 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 4 hours
500
458
QTc(B) (msec)
450
400
350
60
80
100
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
40
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.12
Minimum Post-Baseline Potassium Values Versus Baseline Potassium Values
2.8
2.6
2.4
2.2
2.0
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Minimum (/LLN)
459
Treatment
CONFIDENTIAL
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.2
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Baseline (/LLN)
Note: Shows each subjects minimum value against their baseline value, each divided by the lower limit of normal
Note: Clinical concern level is 0.9xLLN
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
2.2
2.4
2.6
2.8
YM2008/00019/00
B2C109575
0.4
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.13
Box Plot of Minimum Post-Baseline Potassium Values
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
460
YM2008/00019/00
B2C109575
Note: Shows each subjects minimum value divided by the lower limit of normal
Note: Clinical concern level is 0.9xLLN
Note: Graph only shows subjects who were above LLN at baseline
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.14
Maximum Post-Baseline Glucose Values Versus Baseline Glucose Values
4.0
3.5
3.0
CONFIDENTIAL
461
Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Maximum (/ULN)
2.5
2.0
1.5
1.0
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Baseline (/ULN)
Note: Shows each subjects maximum value against their baseline value, each divided by the upper limit of normal
Note: Clinical concern level is 1.5xULN
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
3.5
4.0
YM2008/00019/00
B2C109575
0.5
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.15
Box Plot of Maximum Post-Baseline Glucose Values
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
462
YM2008/00019/00
B2C109575
Note: Shows each subjects maximum value divided by the upper limit of normal
Note: Clinical concern level is 1.5xULN
Note: Graph only shows subjects who were below ULN at baseline
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.16
Mean Fasting Potassium by Time and Treatment
Day: 1
Day: 28
4.35
4.25
4.30
4.20
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
CONFIDENTIAL
463
4.40
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.17
Mean Fasting Glucose by Time and Treatment
Day: 1
Day: 28
5.4
5.3
5.1
5.2
CONFIDENTIAL
464
5.0
4.9
Time (hours)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 8.18
Box Plot of Maximum Increase from Baseline in Pulse Rate (beats/min)
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal.
For further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
465
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 9
Figure 8.101
Potassium Profiles for Subjects with Values >7 (MMOL/L)
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of
the GSK Clincal Study Register.
CONFIDENTIAL
466
YM2008/00019/00
B2C109575
Note: Std. lab is the potassium value from the standard lab dataset
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.1
Summary of Exposure
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Exposure (Days) [1]
n
102
101
101
100
101
102
Mean
25.5
25.7
26.6
26.8
27.0
27.6
SD
7.06
7.03
5.92
5.96
5.17
4.08
Median
29.0
29.0
29.0
29.0
29.0
29.0
Min.
1
1
4
1
5
6
Max.
31
31
35
36
32
31
Range of exposure
102
8 (8%)
4 (4%)
38 (37%)
52 (51%)
101
5 (5%)
8 (8%)
30 (30%)
58 (57%)
101
4 (4%)
4 (4%)
33 (33%)
60 (59%)
100
2 (2%)
6 (6%)
27 (27%)
65 (65%)
101
3 (3%)
2 (2%)
39 (39%)
57 (56%)
102
1 (<1%)
3 (3%)
35 (34%)
63 (62%)
475
YM2008/00019/00
B2C109575
CONFIDENTIAL
n
<=7 days
8-14 days
15-28 days
>=29 days
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 7
Table 8.2
Summary of On-Treatment Adverse Events
(14%)
(12%)
(<1%)
12 (12%)
2 (2%)
8
2
4 (4%)
2 (2%)
2 (2%)
0
1 (<1%)
0
0
0
0
0
0
0
0
(9%)
(9%)
(1%)
(1%)
(<1%)
(<1%)
9
9
1
1
0
0
0
0
0
0
0
0
8 (8%)
7 (7%)
0
1 (<1%)
0
0
0
0
0
0
0
0
10 (10%)
8 (8%)
3 (3%)
1 (<1%)
0
0
0
0
0
0
0
0
(8%)
(2%)
7 (7%)
1 (<1%)
7
3
(7%)
(3%)
3
2
12 (12%)
2 (2%)
2 (2%)
1 (<1%)
2 (2%)
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
2 (2%)
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
1
0
0
0
0
1
1
0
0
0
(<1%)
(<1%)
(<1%)
(<1%)
11
7
1
0
2
0
0
0
0
0
1
1
(11%)
(7%)
(<1%)
(2%)
(1%)
(1%)
(1%)
(3%)
(2%)
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
2
1
1
2
0
0
0
1
0
0
1
1
0
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
YM2008/00019/00
B2C109575
9 (9%)
8 (8%)
2 (2%)
1 (<1%)
0
0
0
0
0
1 (<1%)
0
0
CONFIDENTIAL
476
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 7
Table 8.2
Summary of On-Treatment Adverse Events
(<1%)
(<1%)
(<1%)
5
1
1
0
1
1
1
2
1
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
(<1%)
(<1%)
(2%)
(3%)
(5%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(5%)
7
1
1
1
0
0
1
0
1
1
0
0
0
0
(7%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
4
0
1
0
1
1
0
0
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
1
0
0
(4%)
(4%)
(1%)
(1%)
(1%)
(1%)
(2%)
3 (3%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
7
2
1
1
1
0
1
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
(6%)
(7%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(4%)
YM2008/00019/00
B2C109575
6
0
0
1
1
2
0
0
0
0
0
1
1
1
CONFIDENTIAL
477
Gastrointestinal disorders
Any event
Nausea
Toothache
Abdominal pain upper
Diarrhoea
Dyspepsia
Flatulence
Vomiting
Dry mouth
Abdominal discomfort
Abdominal pain
Colitis
Enteritis
Gastrooesophageal reflux
disease
Hypoaesthesia oral
Mouth ulceration
Peptic ulcer
Stomach discomfort
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 7
Table 8.2
Summary of On-Treatment Adverse Events
478
Investigations
Any event
Blood creatine phosphokinase
increased
6 (6%)
0
0
3 (3%)
1 (<1%)
2 (2%)
0
0
0
0
0
1 (<1%)
0
0
4
2
1
0
1
0
0
1
0
0
0
0
1
0
(4%)
(2%)
(<1%)
1 (<1%)
0
3
2
(3%)
(2%)
(<1%)
(<1%)
(<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
3
1
1
0
0
0
1
0
1
1
0
0
0
1
(3%)
(1%)
(1%)
5 (5%)
1 (<1%)
2
0
(2%)
(1%)
(1%)
(1%)
(1%)
4
0
1
0
1
0
1
1
0
0
0
0
0
0
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
2 (2%)
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
4
0
(4%)
YM2008/00019/00
B2C109575
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 7
Table 8.2
Summary of On-Treatment Adverse Events
4
1
1
1
1
0
0
0
0
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
2 (2%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
1
0
0
0
0
0
1
0
0
(1%)
(1%)
2 (2%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
CONFIDENTIAL
479
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 7
Table 8.2
Summary of On-Treatment Adverse Events
0
1 (<1%)
0
0
Psychiatric disorders
Any event
Insomnia
Anxiety
Middle insomnia
Nervousness
Restlessness
Skin and subcutaneous tissue
disorders
Any event
Dermatitis contact
Pruritus
Rash
(2%)
(2%)
2 (2%)
1 (<1%)
0
2
0
1
(2%)
0
0
0
0
0
0
0
1 (<1%)
1
0
0
0
(1%)
3 (3%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
5
2
2
0
(5%)
(2%)
(2%)
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
2 (2%)
1 (<1%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
(1%)
YM2008/00019/00
B2C109575
2 (2%)
1 (<1%)
0
CONFIDENTIAL
480
Cardiac disorders
Any event
Palpitations
Atrioventricular block
second degree
Bradycardia
Ventricular arrhythmia
Ventricular extrasystoles
Wandering pacemaker
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 7
Table 8.2
Summary of On-Treatment Adverse Events
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
2
2
0
0
0
0
1 (<1%)
1 (<1%)
0
0
Vascular disorders
Any event
Hypertension
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
Eye disorders
Any event
Conjunctivitis
Conjunctivitis allergic
0
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
1
(1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
1
0
1
(1%)
0
0
0
0
0
0
(2%)
(2%)
(1%)
(1%)
YM2008/00019/00
B2C109575
0
0
0
CONFIDENTIAL
481
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 7
Table 8.2
Summary of On-Treatment Adverse Events
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
CONFIDENTIAL
482
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.3
Summary of Post-Treatment Adverse Events
483
2 (2%)
0
1 (<1%)
1 (<1%)
4 (4%)
1 (<1%)
0
1 (<1%)
0
0
0
0
2 (2%)
1 (<1%)
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
1 (<1%)
0
0
0
0
3 (3%)
2 (2%)
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
2
2
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
Gastrointestinal disorders
Any event
Nausea
Toothache
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
(2%)
(2%)
YM2008/00019/00
B2C109575
0
0
0
0
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.3
Summary of Post-Treatment Adverse Events
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
CONFIDENTIAL
484
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.4
Summary of Most Frequent On-Treatment Adverse Events
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Any event
37 (36%)
37 (37%)
34 (34%)
25 (25%)
23 (23%)
31 (30%)
8
2
(8%)
(2%)
12 (12%)
2 (2%)
7 (7%)
1 (<1%)
9
3
4
2
0
0
3
(4%)
(2%)
2 (2%)
1 (<1%)
3 (3%)
0
0
2 (2%)
1 (<1%)
0
2 (2%)
0
0
1
1
0
0
(3%)
(9%)
(3%)
(1%)
(1%)
7
2
(7%)
(2%)
8
2
(8%)
(2%)
0
0
1 (<1%)
0
0
2
3
0
3
0
(2%)
(3%)
485
YM2008/00019/00
B2C109575
(3%)
CONFIDENTIAL
Headache
Upper respiratory tract
infection
Nasopharyngitis
Dizziness
Back pain
Muscle spasms
Dyspnoea
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 3
Table 8.5
Summary of Drug-Related Adverse Events
486
Investigations
Any event
Blood creatine phosphokinase
increased
Blood potassium increased
Blood pressure increased
Electrocardiogram PR
prolongation
Electrocardiogram QT
prolonged
Electrocardiogram T wave
amplitude decreased
Liver function test abnormal
Gastrointestinal disorders
2
1
1
1
1
0
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
3 (3%)
2 (2%)
0
0
0
1 (<1%)
2
2
0
0
0
0
(2%)
(2%)
2
2
0
0
0
0
1 (<1%)
0
2 (2%)
1 (<1%)
3 (3%)
1 (<1%)
2
0
(2%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
1
0
0
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
(1%)
2 (2%)
1 (<1%)
0
2
2
0
1 (<1%)
1 (<1%)
0
1
0
1
(1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
(2%)
(2%)
(1%)
(1%)
(2%)
(2%)
2
0
2
0
0
0
(2%)
(2%)
YM2008/00019/00
B2C109575
Cardiac disorders
Any event
Palpitations
Atrioventricular block
second degree
Ventricular arrhythmia
Ventricular extrasystoles
0
0
0
0
0
0
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 3
Table 8.5
Summary of Drug-Related Adverse Events
2 (2%)
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
0
0
0
1 (<1%)
Psychiatric disorders
Any event
Insomnia
Middle insomnia
Restlessness
1 (<1%)
0
1 (<1%)
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2 (2%)
1 (<1%)
0
1 (<1%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
0
0
0
0
0
CONFIDENTIAL
487
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 3
Table 8.5
Summary of Drug-Related Adverse Events
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
(1%)
(1%)
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
0
0
0
0
0
0
(<1%)
(<1%)
(<1%)
(<1%)
CONFIDENTIAL
488
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.6
Summary of Adverse Events Leading to Permanent Discontinuation of Study drug or
Withdrawal from the Study
0
0
1
1
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
(1%)
(1%)
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0
0
2 (2%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
Psychiatric disorders
Any event
Insomnia
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
YM2008/00019/00
B2C109575
0
0
Investigations
Any event
Electrocardiogram PR
prolongation
Electrocardiogram T wave
amplitude decreased
0
0
CONFIDENTIAL
489
0
0
1 (<1%)
0
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.7
Summary of Pre-Treatment Serious Adverse Events
No data to report
CONFIDENTIAL
490
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.8
Summary of On-Treatment Serious Adverse Events
No data to report
CONFIDENTIAL
491
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.9
Summary of Post-Treatment Serious Adverse Events
No data to report
CONFIDENTIAL
492
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Ear pain
Vertigo
Eye disorders
Conjunctivitis
Conjunctivitis allergic
Conjunctivitis
Allergic Conjunctivitis Flare
up
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain
Abdominal pain upper
abdominal discomfort
abdominal pain
Stomach Ache
epigastric soreness
stomach pain
COLITIS
Diarrhoea
diarrhea
diarrhoe
Dry Mouth
dry mouth
Dyspepsia
Indigestion
heartburn
Colitis
Diarrhoea
Dry mouth
Dyspepsia
YM2008/00019/00
B2C109575
CONFIDENTIAL
493
Ventricular arrhythmia
Ventricular extrasystoles
Wandering pacemaker
Episodic Bradycardia
cardiac palpitations
palpitations
Ventricular Dysrhythmia
Ventricular ectopy
wandering atrial pacemaker
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Fatigue
Feeling jittery
Non-cardiac chest pain
Oedema peripheral
Pyrexia
tiredness
Jittery
non cardiac chest pain
Oedema of legs
Fever
fever
high fever
Right and Left arm pain (due
to blood draws)
Hypersensitivity
Allergy
YM2008/00019/00
B2C109575
Chest pain
CONFIDENTIAL
494
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Acute sinusitis
Bronchitis
495
Gastrointestinal infection
Genital infection
Hepatitis E
Infectious mononucleosis
Influenza
Nasopharyngitis
Pharyngitis
Rhinitis
Sinusitis
YM2008/00019/00
B2C109575
Oral candidiasis
Oral herpes
Otitis media
CONFIDENTIAL
Candidiasis
Eye infection
Gastroenteritis
Acute Sinusitis
Acute Bronchitis
Bronchitis
Thrush
eye-infection
Gasterointeritis
Gastroenteritis
gastro intestinal infection
Gynecological Infection
Hepatitis E
Mononucleosis
Influenza
fLU
flu
Cold
Cold Symptoms
Common cold
Common cold
common cold
oral candidiasis
herpes labialis
Left Otitis Media
Otitis Media Right Ear
Acute pharingitis
Pharyngitis
pharyngitis
rhinitis
Sinus Infection
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Chest injury
Contusion
Excoriation
Face injury
Hand fracture
YM2008/00019/00
B2C109575
Back injury
CONFIDENTIAL
496
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
ALAT(SGPT) elevation
ASAT(SGOT) elevation
CPK serum level elevated
Elevated CPK Levels
Elevated creatinine kinase
elevated total CPK
Elevated glucose on labs
Elevated Potassium
elevated potassium
Elevated blood pressure
Increased blood pressure
Worsening of Elevated blood
pressure
Prolonged PR Interval [245 ms]
YM2008/00019/00
B2C109575
Electrocardiogram PR
prolongation
Electrocardiogram QT prolonged QT prolongation
Electrocardiogram ST-T change ECG ST-T wave abnormalities on
but
we received the result on
CONFIDENTIAL
497
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Blood creatine phosphokinase
increased
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Dehydration
Musculoskeletal and
connective tissue disorders
Arthralgia
498
YM2008/00019/00
B2C109575
Arthralgia metacarpal
phalangeal joint
Arthralgia of right shoulder
Right knee pain
elbow joint pain
joint pain
pain of right hip
Back pain
Backache
Lower back ache
back pain
backache
lower back pain
Bursitis
left shoulder bursitis
(observation)
Flank pain
left flank pain
Intervertebral disc protrusion slipped disk
Muscle spasms
Leg Cramps
calf cramping
cramps
foot cramping
hand cramping
leg cramping
muscle spasm left trapezius
Myalgia
Muscle Aches
Muscle pain lower back right
side
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Dizziness
499
Headache
Paraesthesia
Psychomotor hyperactivity
Restless legs syndrome
YM2008/00019/00
B2C109575
Intercostal neuralgia
Migraine
Dizziness
Lightheadedness
dizziness
lightheaded
Head ache
Headache
Headaches
headach
headache
headache intermittend
hedache exacervation
worsening headache
worsening of headaches
Intercostal neuralgia
Headache Migraine
Migraine
episode of migraine
migraine
migraine headache
Parestheasia in limbs
Hyperactivity "wired"
restless legs
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Anxiety
Proteinuria
PROTEINURIA
Dysmenorrhoea
Menstrual Cramps
Premenstrual syndrome
Pre-menstrual syndrome
Cough
Cough
Insomnia
500
Epistaxis
Nasal congestion
cough
dry troat by night
hoarseness
dyspnea
increased dyspnoe
increased dyspnoea
Nose Bleed
Nose bleed
bleeding nose
Nasal congestion
nasal congestion
worsening nasal congestion
YM2008/00019/00
B2C109575
Dry throat
Dysphonia
Dyspnoea
CONFIDENTIAL
Middle insomnia
Nervousness
Restlessness
Anxiety
anxiety
Insomnia
sleeplessness
nighttime awakenings
nervousness
Intermittant Restlessness
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 9
Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
501
Phlebectomy
Vascular disorders
Hypertension
Arterial hypertension
Worsening of hypertension
arterial hypertension
YM2008/00019/00
B2C109575
CONFIDENTIAL
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Alanine Amino
Placebo
102 Screening
102
23.0
16.05
20.0
6
137
Transferase (IU/L)
Day 14
91
20.6
10.54
17.0
8
59
Day 28
87
19.4
11.52
17.0
6
83
101
Screening
Day 14
Day 28
101
88
85
20.8
18.9
19.2
13.63
8.55
10.54
18.0
17.0
17.0
6
6
6
115
57
77
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
21.0
19.7
20.3
9.76
8.25
8.10
19.0
18.0
19.0
4
6
7
64
40
49
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
24.1
22.5
22.9
17.04
13.86
15.09
18.0
18.0
18.0
5
8
7
91
83
97
25mcg
101
Screening
Day 14
Day 28
101
93
92
20.2
18.7
20.5
15.31
10.16
11.20
16.0
17.0
16.0
5
6
7
131
56
63
50mcg
102
Screening
Day 14
Day 28
101
93
96
21.2
22.2
21.2
13.48
18.34
12.52
17.0
17.0
19.0
5
4
3
103
150
70
CONFIDENTIAL
502
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Albumin (G/L)
Placebo
102 Screening
102
45.3
3.21
45.0
37
53
Day 14
91
43.6
3.28
44.0
36
52
Day 28
87
43.9
3.21
44.0
34
52
Screening
Day 14
Day 28
101
88
85
45.0
43.8
43.6
4.06
3.73
3.74
45.0
44.0
44.0
23
25
27
54
53
51
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
45.4
44.0
44.3
3.18
3.27
3.24
45.0
44.0
44.0
38
36
37
53
51
51
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
45.6
44.1
43.9
2.92
2.94
2.93
45.0
44.0
44.0
37
36
35
52
53
50
25mcg
101
Screening
Day 14
Day 28
101
93
92
45.1
43.7
43.9
2.96
2.51
2.85
45.0
44.0
44.0
37
37
33
52
49
52
50mcg
102
Screening
Day 14
Day 28
101
93
96
45.4
43.5
44.0
2.89
2.92
2.98
45.0
43.0
44.0
37
35
36
55
50
54
CONFIDENTIAL
101
503
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Alkaline Phosphatase
Placebo
102 Screening
102
82.6
57.21
71.5
32
432
(IU/L)
Day 14
91
75.7
47.58
64.0
28
460
Day 28
87
74.8
47.11
67.0
33
447
101
Screening
Day 14
Day 28
101
88
85
74.4
72.1
71.5
27.38
24.03
22.88
69.0
68.0
67.0
24
25
23
177
166
146
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
75.5
72.9
72.4
24.88
24.46
22.59
70.0
66.0
68.0
36
32
38
158
147
138
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
86.3
81.0
77.4
50.84
46.65
38.10
73.0
67.5
70.0
26
27
22
367
363
303
25mcg
101
Screening
Day 14
Day 28
101
93
92
80.9
79.0
80.5
47.28
48.44
49.83
73.0
70.0
71.0
30
35
36
377
376
386
50mcg
102
Screening
Day 14
Day 28
101
93
96
80.3
78.6
78.2
33.68
36.67
33.96
74.0
71.0
72.0
37
32
29
314
308
317
CONFIDENTIAL
504
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Aspartate Amino
Placebo
102 Screening
102
21.8
8.65
20.0
9
87
Transferase (IU/L)
Day 14
91
20.2
5.71
19.0
8
44
Day 28
86
19.9
6.04
18.5
7
38
101
Screening
Day 14
Day 28
101
88
85
21.1
20.8
20.3
8.14
11.66
7.02
19.0
18.0
19.0
10
11
10
70
106
46
6.25mcg
101
Screening
Day 14
Day 28
100
90
88
20.8
21.0
21.3
5.81
7.56
6.10
19.0
19.0
20.0
11
12
10
40
71
39
12.5mcg
100
Screening
Day 14
Day 28
99
88
87
23.0
22.4
22.6
9.81
8.67
9.46
19.0
21.0
20.0
11
12
10
63
62
71
25mcg
101
Screening
Day 14
Day 28
101
91
92
21.8
21.0
21.8
10.06
6.03
7.34
20.0
21.0
20.0
10
11
10
105
43
54
50mcg
102
Screening
Day 14
Day 28
101
90
95
22.3
22.9
23.0
8.36
10.38
10.79
20.0
20.0
21.0
11
12
11
61
74
88
CONFIDENTIAL
505
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
Placebo
102 Screening
102
2.366
0.0862
2.370
2.13
2.56
Day 14
91
2.313
0.0870
2.330
2.05
2.52
Day 28
86
2.304
0.1138
2.320
1.72
2.50
Screening
Day 14
Day 28
101
88
85
2.343
2.313
2.300
0.1027
0.1019
0.1107
2.340
2.320
2.300
2.04
2.00
2.04
2.58
2.54
2.54
6.25mcg
101
Screening
Day 14
Day 28
100
90
88
2.350
2.311
2.305
0.1080
0.1120
0.1110
2.350
2.320
2.310
2.10
2.03
1.89
2.59
2.54
2.56
12.5mcg
100
Screening
Day 14
Day 28
99
88
87
2.375
2.338
2.316
0.1129
0.1184
0.1219
2.360
2.340
2.320
2.14
2.08
1.84
2.96
2.91
2.71
25mcg
101
Screening
Day 14
Day 28
101
91
92
2.353
2.308
2.327
0.0937
0.0929
0.1073
2.350
2.320
2.340
2.09
2.03
1.98
2.54
2.52
2.64
50mcg
102
Screening
Day 14
Day 28
101
90
95
2.353
2.321
2.301
0.1067
0.1089
0.1192
2.350
2.320
2.310
2.03
2.04
1.92
2.56
2.54
2.54
CONFIDENTIAL
101
506
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Chloride (MMOL/L)
Placebo
102 Screening
102 104.2
2.16
104.0
97
110
Day 14
91 104.9
2.23
105.0
99
109
Day 28
87 105.0
2.26
105.0
98
111
Screening
Day 14
Day 28
101
88
85
103.9
104.7
104.8
2.25
2.35
2.34
104.0
105.0
105.0
98
98
97
109
109
109
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
104.0
105.0
104.7
2.06
2.09
2.25
104.0
105.0
104.0
98
99
97
109
110
110
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
104.3
104.9
104.9
2.15
2.43
2.17
104.0
105.0
105.0
99
93
98
111
110
109
25mcg
101
Screening
Day 14
Day 28
101
93
92
104.5
105.4
105.1
1.82
2.10
2.37
104.0
106.0
105.0
100
101
99
110
110
110
50mcg
102
Screening
Day 14
Day 28
101
93
96
104.2
105.0
105.2
2.45
2.46
2.77
104.0
105.0
105.0
99
98
97
110
110
112
CONFIDENTIAL
101
507
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Creatine Kinase (IU/L) Placebo
102 Screening
102 121.4
88.61
101.0
30
628
Day 14
91 110.4
61.16
92.0
26
371
Day 28
87 116.8
75.68
98.0
32
509
Screening
Day 14
Day 28
101
88
85
124.6
157.5
148.7
74.95
177.11
196.10
104.0
114.5
107.0
29
29
26
474
1395
1489
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
137.0
151.8
140.7
108.48
106.70
89.41
112.5
123.0
121.0
33
34
36
720
579
563
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
130.3
194.5
161.3
79.80
452.51
129.85
109.0
114.0
132.0
35
31
37
465
4280
762
25mcg
101
Screening
Day 14
Day 28
101
93
92
165.7
176.0
161.9
231.67
212.23
147.36
109.0
112.0
113.5
36
33
33
1988
1683
917
50mcg
102
Screening
Day 14
Day 28
101
93
96
129.1
138.4
252.2
120.45
141.68
1235.48
93.0
101.0
108.5
32
38
43
869
1194
12213
CONFIDENTIAL
101
508
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Creatinine (UMOL/L)
Placebo
102 Screening
102
82.6
13.94
80.0
52
124
Day 14
91
82.2
15.38
82.0
53
133
Day 28
87
82.1
14.59
80.0
53
129
Screening
Day 14
Day 28
101
88
85
84.5
86.5
84.5
14.64
16.36
15.83
83.0
84.0
85.0
53
56
53
133
135
124
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
83.1
84.4
83.8
16.32
17.50
18.28
83.5
84.0
81.0
47
47
45
133
141
150
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
81.5
82.0
81.4
15.19
16.56
14.13
80.0
80.0
80.0
53
49
53
141
133
133
25mcg
101
Screening
Day 14
Day 28
101
93
92
81.6
82.8
80.7
13.40
18.51
14.00
80.0
80.0
80.0
55
53
53
124
192
124
50mcg
102
Screening
Day 14
Day 28
101
92
96
81.3
82.6
81.4
14.33
16.56
14.89
80.0
80.0
80.0
44
53
53
113
140
130
CONFIDENTIAL
101
509
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Direct Bilirubin
Placebo
102 Screening
102
2.0
0.99
2.0
0
6
(UMOL/L)
Day 14
87
1.9
0.99
2.0
0
4
Day 28
87
1.7
0.85
2.0
0
4
101
Screening
Day 14
Day 28
101
86
85
1.9
2.0
1.7
1.05
1.14
1.02
2.0
2.0
2.0
0
0
0
6
6
4
6.25mcg
101
Screening
Day 14
Day 28
100
89
89
2.1
1.8
1.9
1.17
1.13
1.04
2.0
2.0
2.0
0
0
0
6
6
8
12.5mcg
100
Screening
Day 14
Day 28
99
89
89
2.1
1.9
1.8
1.15
1.01
1.02
2.0
2.0
2.0
0
0
0
6
5
6
25mcg
101
Screening
Day 14
Day 28
101
92
91
2.0
1.7
1.8
1.12
0.99
0.96
2.0
2.0
2.0
0
0
0
6
4
6
50mcg
102
Screening
Day 14
Day 28
101
92
96
1.9
1.8
1.8
0.98
1.13
0.88
2.0
2.0
2.0
0
0
0
4
8
4
CONFIDENTIAL
510
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Gamma Glutamyl
Placebo
102 Screening
102
29.8
27.15
21.5
8
223
Transferase (IU/L)
Day 14
91
29.4
35.08
21.0
9
300
Day 28
87
29.7
33.54
22.0
9
277
101
Screening
Day 14
Day 28
101
88
85
31.1
30.0
28.5
25.32
23.25
19.81
23.0
22.0
22.0
10
10
11
149
154
120
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
31.3
28.9
29.7
24.83
23.14
22.61
23.0
21.0
23.0
7
7
9
130
119
120
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
35.5
32.1
32.7
31.65
28.02
26.08
28.0
27.5
27.0
6
6
7
232
216
223
25mcg
101
Screening
Day 14
Day 28
101
93
92
28.9
27.6
29.1
21.96
19.43
20.88
21.0
20.0
20.0
8
6
7
119
88
109
50mcg
102
Screening
Day 14
Day 28
101
93
96
34.8
31.9
33.0
42.34
25.46
28.90
25.0
24.0
26.0
9
8
8
398
170
222
CONFIDENTIAL
511
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Glucose (MMOL/L)
Placebo
102 Screening
102
5.19
1.870
5.00
3.0
22.8
Day 14
91
5.14
1.538
4.80
2.9
15.9
Day 28
87
5.02
1.370
4.80
2.7
13.4
Screening
Day 14
Day 28
101
87
85
4.89
5.46
5.05
0.849
2.086
1.528
4.90
5.10
4.80
1.3
2.9
2.3
7.3
22.0
14.5
6.25mcg
101
Screening
Day 14
Day 28
100
91
88
4.94
5.11
4.86
0.696
0.761
0.757
4.90
4.90
4.70
2.7
3.4
2.0
8.0
8.5
8.2
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
5.12
5.40
5.06
0.851
1.915
1.062
5.10
5.10
4.90
3.4
3.6
1.9
9.6
21.1
11.5
25mcg
101
Screening
Day 14
Day 28
101
93
92
5.16
5.07
4.96
0.792
0.950
1.191
5.10
4.90
4.80
3.3
3.0
2.7
9.9
8.3
14.0
50mcg
102
Screening
Day 14
Day 28
101
91
94
5.07
5.55
5.10
1.033
2.138
1.749
5.00
5.00
4.80
2.6
3.3
2.6
11.2
20.9
17.0
CONFIDENTIAL
101
512
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Indirect Bilirubin
Placebo
102 Screening
102
7.3
3.62
6.0
2
30
(UMOL/L)
Day 14
87
6.5
3.08
6.0
2
20
Day 28
87
6.9
2.70
6.0
3
16
101
Screening
Day 14
Day 28
101
86
85
7.5
6.9
7.0
4.14
4.04
3.68
6.0
6.0
6.0
2
1
2
30
22
24
6.25mcg
101
Screening
Day 14
Day 28
100
89
89
8.0
7.2
6.7
4.88
4.90
5.19
6.0
6.0
6.0
4
2
2
36
42
48
12.5mcg
100
Screening
Day 14
Day 28
99
89
89
8.0
7.1
7.3
4.25
3.50
4.26
7.0
6.0
6.0
2
2
2
28
21
23
25mcg
101
Screening
Day 14
Day 28
101
92
91
7.5
6.7
6.9
4.10
3.63
3.40
6.0
6.0
6.0
3
2
2
23
20
21
50mcg
102
Screening
Day 14
Day 28
101
92
96
7.1
6.1
6.3
2.83
2.66
2.80
6.0
6.0
6.0
2
0
2
18
15
17
CONFIDENTIAL
513
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Lactate Dehydrogenase
Placebo
102 Screening
102 162.4
30.40
157.5
79
243
(IU/L)
Day 14
91 159.3
32.91
153.0
78
268
Day 28
86 156.1
32.63
151.5
78
292
101
Screening
Day 14
Day 28
101
88
85
161.5
157.3
156.8
29.40
28.74
29.27
154.0
153.0
156.0
105
107
93
272
223
247
6.25mcg
101
Screening
Day 14
Day 28
100
90
88
162.1
160.0
162.5
27.79
25.25
29.01
156.0
160.5
159.0
100
108
110
230
231
258
12.5mcg
100
Screening
Day 14
Day 28
99
88
87
161.3
162.8
166.9
31.43
35.72
32.19
158.0
156.0
164.0
85
87
78
240
277
251
25mcg
101
Screening
Day 14
Day 28
101
91
92
163.1
164.3
165.4
35.51
37.95
36.56
156.0
159.0
161.0
99
106
105
280
308
291
50mcg
102
Screening
Day 14
Day 28
101
90
95
161.5
157.4
160.9
33.67
34.10
49.59
160.0
153.0
154.0
108
100
93
273
310
509
CONFIDENTIAL
514
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Potassium (MMOL/L)
Placebo
102 Screening
102
4.20
0.425
4.20
3.4
5.8
Day 14
91
4.28
0.665
4.20
3.2
8.8
Day 28
86
4.31
0.524
4.20
3.7
6.6
Screening
Day 14
Day 28
101
88
85
4.19
4.16
4.19
0.345
0.333
0.393
4.10
4.10
4.10
3.3
3.5
3.5
5.3
5.0
5.9
6.25mcg
101
Screening
Day 14
Day 28
100
90
88
4.14
4.17
4.18
0.368
0.395
0.364
4.10
4.10
4.20
3.3
3.2
3.4
5.6
5.3
5.7
12.5mcg
100
Screening
Day 14
Day 28
99
88
87
4.18
4.19
4.18
0.499
0.361
0.471
4.10
4.15
4.10
3.5
3.6
3.3
7.8
5.3
6.1
25mcg
101
Screening
Day 14
Day 28
101
91
92
4.16
4.25
4.29
0.354
0.485
0.515
4.10
4.20
4.20
3.3
3.1
3.1
5.3
6.9
6.9
50mcg
102
Screening
Day 14
Day 28
101
90
95
4.19
4.18
4.25
0.493
0.361
0.443
4.10
4.15
4.20
3.2
3.5
3.4
5.8
5.5
5.5
CONFIDENTIAL
101
515
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Sodium (MMOL/L)
Placebo
102 Screening
102 140.5
1.83
140.0
136
146
Day 14
91 140.5
2.10
140.0
136
147
Day 28
87 140.5
2.15
141.0
136
147
Screening
Day 14
Day 28
101
88
85
140.2
140.1
140.2
1.70
2.07
1.85
140.0
140.0
140.0
136
136
135
145
147
145
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
140.5
140.4
140.2
2.09
2.10
2.58
140.5
140.0
140.0
136
135
133
147
146
151
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
140.4
140.1
140.2
1.82
1.96
2.18
140.0
140.0
140.0
137
133
134
146
145
146
25mcg
101
Screening
Day 14
Day 28
101
93
92
140.7
140.8
140.6
1.99
1.65
1.93
141.0
141.0
141.0
136
137
136
146
145
147
50mcg
102
Screening
Day 14
Day 28
101
93
96
140.4
140.0
140.4
2.11
1.84
2.30
140.0
140.0
140.0
135
136
135
145
145
148
CONFIDENTIAL
101
516
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Total Bilirubin
Placebo
102 Screening
102
9.1
4.47
8.0
3
38
(UMOL/L)
Day 14
91
8.2
3.85
7.0
4
24
Day 28
87
8.2
3.24
7.0
4
18
101
Screening
Day 14
Day 28
101
88
85
9.2
8.7
8.5
5.14
4.86
4.32
8.0
7.0
7.0
3
2
4
38
28
28
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
9.9
8.8
8.4
5.86
5.86
6.02
8.0
8.0
7.0
4
3
3
42
50
56
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
9.8
8.8
8.9
5.06
4.31
4.98
8.0
7.0
7.0
4
4
3
30
26
27
25mcg
101
Screening
Day 14
Day 28
101
93
92
9.2
8.2
8.4
5.00
4.22
4.15
8.0
6.0
7.0
4
4
4
28
24
25
50mcg
102
Screening
Day 14
Day 28
101
93
96
8.8
7.7
7.8
3.58
3.19
3.38
8.0
7.0
6.5
4
4
3
22
19
21
CONFIDENTIAL
517
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Total Protein (G/L)
Placebo
102 Screening
102
73.7
3.98
74.0
64
83
Day 14
91
70.8
3.84
71.0
63
81
Day 28
87
71.4
3.92
72.0
62
78
Screening
Day 14
Day 28
101
88
85
73.2
70.5
70.3
4.44
4.21
4.79
74.0
70.0
70.0
58
62
58
82
82
85
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
73.2
70.5
71.0
4.12
4.32
4.44
73.0
70.0
71.0
64
62
60
84
83
83
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
73.5
70.6
70.6
3.84
4.19
4.34
74.0
71.0
71.0
62
61
60
80
80
79
25mcg
101
Screening
Day 14
Day 28
101
93
92
73.5
70.4
71.3
3.87
3.81
4.46
74.0
70.0
71.0
64
62
55
85
79
83
50mcg
102
Screening
Day 14
Day 28
101
93
96
74.3
71.0
71.8
4.40
4.44
4.37
74.0
71.0
72.0
66
59
59
85
83
89
CONFIDENTIAL
101
518
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Urea (MMOL/L)
Placebo
102 Screening
102
5.33
1.482
5.15
2.1
10.5
Day 14
91
5.40
1.504
5.30
1.7
8.8
Day 28
87
5.50
1.556
5.50
3.0
10.5
Screening
Day 14
Day 28
101
88
85
5.58
5.85
5.72
1.493
1.705
1.465
5.50
5.50
5.50
3.0
2.9
3.4
9.6
10.7
11.5
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
5.63
5.51
5.58
1.421
1.525
1.556
5.50
5.50
5.50
3.0
2.0
2.5
9.5
8.9
9.5
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
5.37
5.58
5.40
1.620
1.640
1.786
5.00
5.50
5.10
2.5
3.0
2.5
10.2
11.5
12.0
25mcg
101
Screening
Day 14
Day 28
101
93
92
5.46
5.56
5.56
1.570
1.521
1.451
5.40
5.50
5.50
2.5
2.5
2.5
11.0
10.2
9.6
50mcg
102
Screening
Day 14
Day 28
101
93
96
5.13
5.36
5.54
1.471
1.414
1.487
5.00
5.40
5.50
2.0
3.0
3.0
9.5
9.3
9.5
CONFIDENTIAL
101
519
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 19
Table 8.11
Summary of Chemistry Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Uric acid (UMOL/L)
Placebo
102 Screening
102 334.2
79.48
333.5
124
536
Day 14
91 324.5
82.93
322.0
150
541
Day 28
87 329.3
78.70
335.0
148
490
Screening
Day 14
Day 28
101
88
85
330.5
344.8
339.7
69.05
87.87
82.67
332.0
337.5
330.0
162
150
140
470
777
582
6.25mcg
101
Screening
Day 14
Day 28
100
91
89
331.6
337.5
341.4
81.90
88.75
88.59
333.5
339.0
343.0
162
146
191
528
630
610
12.5mcg
100
Screening
Day 14
Day 28
99
90
89
329.5
327.4
323.6
76.50
78.79
77.41
330.0
320.0
330.0
150
160
170
497
520
490
25mcg
101
Screening
Day 14
Day 28
101
93
92
311.6
323.0
317.8
76.95
90.13
80.99
307.0
320.0
313.5
180
150
170
618
668
624
50mcg
102
Screening
Day 14
Day 28
101
92
96
322.5
330.4
327.4
85.13
87.13
86.37
318.0
326.5
320.0
150
140
170
530
516
520
CONFIDENTIAL
101
520
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
2
(2%)
88
1
(1%)
91
0
Day 28
n
High
87
2
(2%)
85
2
(2%)
89
1
99
521
High
99
(3%)
(1%)
101
(3%)
90
5
(6%)
93
3
(3%)
93
5
(5%)
89
5
(6%)
92
2
(2%)
96
5
(5%)
98
(2%)
(9%)
99
(5%)
(6%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
100
CONFIDENTIAL
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
2
0
(2%)
88
3
1
(3%)
(1%)
91
2
0
(2%)
90
1
0
Day 28
n
High
Low
87
1
0
(1%)
85
1
1
(1%)
(1%)
89
1
0
(1%)
89
0
0
92
1
0
99
98
100
High
Low
2
0
99
(2%)
3
1
101
(3%)
(1%)
3
0
(3%)
(1%)
93
0
0
1
0
93
0
0
(1%)
96
1
0
(1%)
99
(1%)
1
0
(1%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
1
0
(1%)
CONFIDENTIAL
522
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
0
0
88
1
0
(1%)
91
4
0
(4%)
90
2
0
(2%)
93
1
0
(1%)
93
2
0
(2%)
Day 28
n
High
Low
87
0
0
85
1
0
(1%)
89
2
0
(2%)
89
1
0
(1%)
92
1
0
(1%)
96
2
0
(2%)
99
99
0
0
2
0
High
Low
101
(2%)
4
0
98
(4%)
(3%)
1
0
99
(1%)
2
0
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
3
0
100
CONFIDENTIAL
523
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
Day 28
n
High
524
High
88
3
(3%)
90
1
86
0
85
2
(2%)
99
99
(1%)
(1%)
(5%)
88
3
(3%)
91
1
(1%)
90
4
(4%)
88
0
87
4
(5%)
92
1
(1%)
95
7
(7%)
100
98
(1%)
(2%)
(6%)
99
(2%)
(9%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
100
CONFIDENTIAL
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
525
91
0
1
n
High
Low
86
0
4
99
High
Low
0
5
(1%)
88
0
3
(5%)
85
0
3
(3%)
90
0
6
(4%)
88
0
2
99
(5%)
0
6
(7%)
88
2
2
(2%)
(2%)
91
0
1
(2%)
87
2
3
(2%)
(3%)
92
1
4
100
(6%)
0
7
98
(7%)
(3%)
(1%)
(4%)
95
0
7
(7%)
100
(2%)
(5%)
1
4
99
(1%)
(4%)
0
8
(8%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
5
(1%)
90
0
3
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
0
(1%)
88
4
0
(5%)
91
3
0
(3%)
90
4
1
Day 28
n
High
Low
87
3
0
(3%)
85
4
0
(5%)
89
6
0
(7%)
89
4
0
99
High
Low
5
0
99
(5%)
8
0
101
(8%)
8
0
(4%)
(1%)
(4%)
98
(8%)
(5%)
93
8
0
(9%)
92
6
0
(7%)
96
8
0
(8%)
100
(8%)
(1%)
10
0
99
(10%)
12
0
(12%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
8
1
93
5
0
CONFIDENTIAL
526
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
4
(4%)
88
13
(15%)
91
15
(16%)
90
17
(19%)
93
19
(20%)
93
9
(10%)
Day 28
n
High
87
8
(9%)
85
7
(8%)
89
13
(15%)
89
18
(20%)
92
18
(20%)
96
12
(13%)
99
High
11
99
(11%)
16
101
(16%)
19
98
(19%)
(24%)
26
99
(26%)
17
(17%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
24
100
CONFIDENTIAL
527
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
0
(1%)
88
1
0
Day 28
n
High
Low
87
1
0
(1%)
99
High
Low
1
0
(1%)
91
2
0
(2%)
90
1
0
(1%)
93
2
0
85
0
0
89
2
0
(2%)
89
1
0
(1%)
99
101
1
0
(1%)
(1%)
3
0
98
(3%)
(2%)
(1%)
92
0
0
96
1
0
(1%)
100
99
3
0
(3%)
2
0
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
0
92
1
0
(2%)
CONFIDENTIAL
528
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
87
0
86
0
89
0
Day 28
n
High
87
0
85
0
89
1
99
98
100
High
(1%)
(1%)
92
0
92
1
89
0
91
0
96
0
98
99
99
(1%)
(1%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
89
0
CONFIDENTIAL
529
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
7
(8%)
88
8
(9%)
91
10
(11%)
90
9
(10%)
93
10
(11%)
93
11
(12%)
Day 28
n
High
87
8
(9%)
85
6
(7%)
89
12
(13%)
89
9
(10%)
92
9
(10%)
96
11
(11%)
99
High
10
99
(10%)
101
(9%)
14
98
(14%)
(13%)
13
99
(13%)
13
(13%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
13
100
CONFIDENTIAL
530
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
5
4
(5%)
(4%)
87
6
2
(7%)
(2%)
91
1
1
(1%)
(1%)
90
7
2
(8%)
(2%)
93
6
6
(6%)
(6%)
91
9
3
(10%)
(3%)
Day 28
n
High
Low
87
5
6
(6%)
(7%)
85
6
5
(7%)
(6%)
88
2
2
(2%)
(2%)
89
5
3
(6%)
(3%)
92
3
3
(3%)
(3%)
94
4
5
(4%)
(5%)
99
High
Low
10
8
99
(10%)
(8%)
11
5
101
(11%)
(5%)
4
4
98
(4%)
(4%)
(10%)
(5%)
9
8
98
(9%)
(8%)
10
8
(10%)
(8%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
10
5
100
CONFIDENTIAL
531
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
87
0
86
0
Day 28
n
High
87
0
85
1
99
98
High
(1%)
89
1
(1%)
89
0
89
1
(1%)
89
1
100
(1%)
(1%)
98
(1%)
(2%)
92
0
91
0
96
0
99
99
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
92
0
CONFIDENTIAL
532
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
(1%)
88
0
90
0
Day 28
n
High
86
1
(1%)
85
0
88
1
99
99
100
High
(2%)
(1%)
88
3
(3%)
91
3
(3%)
90
3
(3%)
87
1
(1%)
92
3
(3%)
95
3
(3%)
98
(1%)
(4%)
99
(4%)
(5%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
100
CONFIDENTIAL
533
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
3
2
Day 28
n
High
Low
86
3
0
99
High
Low
5
2
(3%)
(2%)
(3%)
88
0
0
85
2
0
(2%)
99
(5%)
(2%)
2
0
90
0
2
(2%)
88
0
0
88
1
1
(1%)
(1%)
87
2
1
100
(2%)
1
2
(2%)
(1%)
98
(1%)
(2%)
(3%)
(1%)
90
1
0
92
3
2
(3%)
(2%)
95
3
1
100
(2%)
(1%)
4
2
(1%)
(3%)
(1%)
99
(4%)
(2%)
4
2
(4%)
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
1
91
3
1
CONFIDENTIAL
534
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
535
91
1
0
(1%)
88
1
0
n
High
Low
87
1
0
(1%)
85
0
0
89
1
2
99
99
101
High
Low
2
0
(2%)
1
0
(1%)
(1%)
91
0
0
1
2
90
0
1
(1%)
(2%)
89
0
1
(1%)
93
0
0
(1%)
92
1
0
98
(<1%)
(2%)
(1%)
100
(2%)
1
0
96
2
0
(2%)
99
(1%)
2
0
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
2
93
0
0
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
Day 28
n
High
536
High
88
3
(3%)
91
2
(2%)
90
1
(1%)
93
1
(1%)
93
0
87
0
85
2
(2%)
89
1
(1%)
89
3
(3%)
92
1
(1%)
96
0
99
99
(1%)
(1%)
101
(3%)
98
(2%)
(5%)
99
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
100
CONFIDENTIAL
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
537
91
0
0
88
0
0
91
0
0
90
0
0
93
0
0
93
0
1
(1%)
n
High
Low
87
0
0
85
0
2
89
0
0
89
0
0
92
0
1
96
1
1
(1%)
(1%)
99
99
101
98
100
0
0
0
2
0
0
0
0
0
1
High
Low
(2%)
(2%)
99
(1%)
1
2
(1%)
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
(1%)
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
0
1
Day 28
n
High
Low
87
4
0
99
High
Low
4
1
(1%)
(5%)
88
7
0
(8%)
91
0
1
85
1
0
(1%)
89
1
0
99
(4%)
(1%)
7
0
(1%)
(1%)
101
(7%)
1
1
90
3
0
89
3
1
(3%)
(3%)
(1%)
98
(<1%)
(<1%)
(2%)
(1%)
93
1
0
(1%)
92
1
1
(1%)
(1%)
96
1
0
(1%)
100
(4%)
(1%)
3
1
99
(3%)
(1%)
2
0
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
4
1
93
2
1
CONFIDENTIAL
538
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range
91
1
0
Day 28
n
High
Low
87
0
1
99
High
Low
2
1
(1%)
(1%)
88
3
0
85
4
1
(3%)
(5%)
(1%)
99
(2%)
(1%)
5
1
91
3
1
89
4
0
(3%)
(1%)
(4%)
101
(5%)
(1%)
6
1
90
2
2
89
1
0
(2%)
(2%)
(1%)
98
(6%)
(<1%)
(4%)
92
2
2
(2%)
(2%)
92
3
0
(3%)
96
2
2
(2%)
(2%)
100
(2%)
(2%)
5
1
99
(5%)
(1%)
4
3
(4%)
(3%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
2
93
4
0
CONFIDENTIAL
539
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Alanine Amino Transferase (IU/L)
n
91
88
91
90
93
93
To Normal or No Change
89 (98%)
88 (100%)
90 (99%)
89 (99%)
92 (99%)
90 (97%)
To High
2
(2%)
0
0
0
1
(1%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
91
0
91 (100%)
0
0
88
0
88 (100%)
0
0
91
90
1
0
88
85
3
0
(99%)
(1%)
(99%)
(1%)
88
0
87
1
0
(99%)
(1%)
(97%)
(3%)
91
0
90
0
1
(1%)
90
0
89
0
1
91
0
87
3
1
(96%)
(3%)
(1%)
90
0
89
0
1
90
88
1
1
(98%)
(1%)
(1%)
88
86
1
1
(99%)
(99%)
(1%)
(99%)
(1%)
(98%)
(1%)
(1%)
93
0
93 (100%)
0
0
93
0
92
0
1
93
0
93 (100%)
0
0
93
0
91
1
1
(98%)
(1%)
(1%)
91
90
1
0
90
86
3
1
(96%)
(3%)
(1%)
(99%)
(1%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
91
0
90
1
0
CONFIDENTIAL
540
Albumin (G/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
n
91
88
90
88
91
90
To Low
1
(1%)
3
(3%)
6
(7%)
2
(2%)
0
3
(3%)
To Normal or No Change
90 (99%)
85 (97%)
83 (92%)
84 (95%)
91 (100%)
86 (96%)
To High
0
0
0
1
(1%)
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
91
89
2
0
Creatinine (UMOL/L)
n
To Low
To Normal or No Change
To High
Missing
91
0
90
1
0
(99%)
(1%)
(98%)
(2%)
(99%)
(1%)
88
0
84
4
0
88
81
7
0
88
0
87
1
0
(95%)
(5%)
(92%)
(8%)
(99%)
(1%)
91
0
87
3
1
91
84
6
1
91
0
90
0
1
(96%)
(3%)
(1%)
90
1
87
1
1
(1%)
(97%)
(1%)
(1%)
93
0
89
4
0
(92%)
(7%)
(1%)
90
80
9
1
(89%)
(10%)
(1%)
93
83
10
0
(98%)
(1%)
(1%)
93
0
91
2
0
(99%)
(1%)
90
0
88
1
1
(96%)
(4%)
(89%)
(11%)
(98%)
(2%)
93
0
87
5
1
(94%)
(5%)
(1%)
93
85
7
1
(91%)
(8%)
(1%)
93
0
90
1
2
(97%)
(1%)
(2%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
91
0
90
1
0
CONFIDENTIAL
541
Chloride (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Direct Bilirubin (UMOL/L)
n
87
86
89
89
92
92
To Normal or No Change
87 (100%)
86 (100%)
88 (99%)
88 (99%)
92 (100%)
90 (98%)
To High
0
0
0
0
0
1
(1%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
(98%)
(2%)
88
87
1
0
Glucose (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
91
2
85
4
0
(2%)
(93%)
(4%)
88
0
81
6
1
87
87 (100%)
0
0
(99%)
(1%)
91
89
1
1
(92%)
(7%)
(1%)
91
1
89
0
1
86
86 (100%)
0
0
89
88
0
1
(98%)
(1%)
(1%)
(1%)
(98%)
(1%)
(99%)
(1%)
90
86
3
1
(96%)
(3%)
(1%)
93
92
1
0
(99%)
(1%)
93
90
2
1
(97%)
(2%)
(1%)
90
2
81
6
1
(2%)
(90%)
(7%)
(1%)
93
6
81
6
0
(6%)
(87%)
(6%)
93
2
80
8
3
(2%)
(86%)
(9%)
(3%)
92
92 (100%)
0
0
92
91
0
1
89
88
0
1
(99%)
(1%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
91
89
2
0
CONFIDENTIAL
542
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lactate Dehydrogenase (IU/L)
n
91
88
90
88
91
90
To Normal or No Change
90 (99%)
88 (100%)
89 (99%)
84 (95%)
89 (98%)
87 (97%)
To High
1
(1%)
0
0
3
(3%)
2
(2%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
Sodium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
91
0
90
1
0
91
91 (100%)
0
0
(2%)
(96%)
(2%)
(99%)
(1%)
88
0
88 (100%)
0
0
90
2
87
0
1
88
0
87
1
0
91
0
90
0
1
(99%)
(1%)
88
88 (100%)
0
0
91
90
0
1
(2%)
(97%)
(1%)
(99%)
(1%)
(99%)
(1%)
88
0
87
0
1
90
1
88
0
1
90
88
1
1
(99%)
(1%)
91
0
88
3
0
(97%)
(3%)
90
0
88
1
1
(1%)
93
0
93 (100%)
0
0
93
0
92
0
1
(98%)
(1%)
(1%)
93
93 (100%)
0
0
93
92
0
1
(1%)
(98%)
(98%)
(1%)
(1%)
(99%)
(1%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
91
2
87
2
0
CONFIDENTIAL
543
Potassium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Total Protein (G/L)
n
91
88
91
90
93
93
To Low
0
0
0
0
0
1
(1%)
To Normal or No Change
91 (100%)
88 (100%)
90 (99%)
89 (99%)
93 (100%)
91 (98%)
To High
0
0
0
0
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
91
0
91 (100%)
0
0
88
0
83
5
0
91
0
91 (100%)
0
0
88
0
85
3
0
(94%)
(6%)
(97%)
(3%)
91
1
89
0
1
91
1
87
2
1
(1%)
90
0
87
2
1
(97%)
(2%)
(1%)
93
1
91
1
0
(1%)
(96%)
(2%)
(1%)
90
2
86
1
1
(2%)
(96%)
(1%)
(1%)
93
0
90
3
0
(1%)
(98%)
(1%)
(98%)
(1%)
(97%)
(3%)
93
0
91
1
1
(98%)
(1%)
(1%)
93
2
87
2
2
(2%)
(94%)
(2%)
(2%)
YM2008/00019/00
B2C109575
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
CONFIDENTIAL
544
Urea (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Alanine Amino Transferase (IU/L)
n
87
85
89
89
92
96
To Normal or No Change
86 (99%)
84 (99%)
87 (98%)
87 (98%)
91 (99%)
93 (97%)
To High
1
(1%)
1
(1%)
1
(1%)
1
(1%)
1
(1%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
85
0
85 (100%)
0
0
89
0
87
1
1
87
0
87 (100%)
0
0
85
0
85 (100%)
0
0
89
0
87
1
1
86
86 (100%)
0
0
85
83
2
0
88
87
0
1
(98%)
(2%)
(98%)
(1%)
(1%)
89
0
88
0
1
(98%)
(1%)
(1%)
89
0
88
0
1
(99%)
(1%)
87
83
3
1
(99%)
(1%)
(99%)
(1%)
(95%)
(3%)
(1%)
92
0
92 (100%)
0
0
96
0
94
1
1
(98%)
(1%)
(1%)
92
0
92 (100%)
0
0
96
0
94
1
1
(98%)
(1%)
(1%)
92
91
1
0
95
89
5
1
(94%)
(5%)
(1%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
0
87 (100%)
0
0
CONFIDENTIAL
545
Albumin (G/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
n
86
85
88
87
92
95
To Low
4
(5%)
3
(4%)
2
(2%)
3
(3%)
2
(2%)
6
(6%)
To Normal or No Change
82 (95%)
82 (96%)
85 (97%)
82 (94%)
89 (97%)
88 (93%)
To High
0
0
0
1
(1%)
1
(1%)
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
87
83
4
0
Creatinine (UMOL/L)
n
To Low
To Normal or No Change
To High
Missing
87
0
86
1
0
(97%)
(3%)
(95%)
(5%)
(99%)
(1%)
85
0
81
4
0
89
0
83
5
1
(98%)
(2%)
89
84
4
1
85
0
85 (100%)
0
0
89
0
87
1
1
85
83
2
0
(95%)
(5%)
(93%)
(6%)
(1%)
89
0
84
4
1
(94%)
(4%)
(1%)
92
0
86
6
0
(94%)
(4%)
(1%)
89
80
8
1
(90%)
(9%)
(1%)
92
83
9
0
(98%)
(1%)
(1%)
89
0
88
0
1
(99%)
(1%)
96
0
90
5
1
(94%)
(5%)
(1%)
(90%)
(10%)
96
89
6
1
(93%)
(6%)
(1%)
92
0
92 (100%)
0
0
96
0
95
0
1
(93%)
(7%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
0
84
3
0
CONFIDENTIAL
546
Chloride (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Direct Bilirubin (UMOL/L)
n
87
85
89
89
91
96
To Normal or No Change
87 (100%)
85 (100%)
87 (98%)
88 (99%)
91 (100%)
95 (99%)
To High
0
0
1
(1%)
0
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
(99%)
(1%)
85
84
1
0
(99%)
(1%)
89
86
2
1
Glucose (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
87
3
80
4
0
(3%)
(92%)
(5%)
85
1
78
6
0
(1%)
(92%)
(7%)
89
0
85
2
2
87
87 (100%)
0
0
85
84
1
0
(99%)
(1%)
89
88
0
1
(97%)
(2%)
(1%)
89
85
3
1
(96%)
(3%)
(1%)
92
89
3
0
(97%)
(3%)
96
93
2
1
(97%)
(2%)
(1%)
(96%)
(2%)
(2%)
89
3
81
4
1
(3%)
(91%)
(4%)
(1%)
92
3
87
2
0
(3%)
(95%)
(2%)
96
5
85
3
3
(5%)
(89%)
(3%)
(3%)
89
87
1
1
(98%)
(1%)
(1%)
91
91 (100%)
0
0
96
95
0
1
(99%)
(1%)
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
86
1
0
CONFIDENTIAL
547
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lactate Dehydrogenase (IU/L)
n
86
85
88
87
92
95
To Normal or No Change
85 (99%)
85 (100%)
86 (98%)
85 (98%)
90 (98%)
92 (97%)
To High
1
(1%)
0
1
(1%)
1
(1%)
2
(2%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
Sodium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
87
0
86
1
0
87
87 (100%)
0
0
(97%)
(3%)
(99%)
(1%)
85
0
83
2
0
88
1
85
1
1
(1%)
(97%)
(1%)
(1%)
87
1
83
2
1
85
0
85 (100%)
0
0
89
2
85
1
1
(2%)
(96%)
(1%)
(1%)
89
1
87
0
1
85
85 (100%)
0
0
89
88
0
1
(98%)
(2%)
(99%)
(1%)
89
86
2
1
(1%)
(95%)
(2%)
(1%)
(1%)
(98%)
(1%)
(97%)
(2%)
(1%)
92
1
88
3
0
92
0
91
1
0
(1%)
(96%)
(3%)
(99%)
(1%)
92
92 (100%)
0
0
95
1
90
3
1
(1%)
(95%)
(3%)
(1%)
96
0
93
2
1
(97%)
(2%)
(1%)
96
95
0
1
(99%)
(1%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
86
0
83
3
0
CONFIDENTIAL
548
Potassium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 10
Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Total Protein (G/L)
n
87
85
89
89
92
96
To Low
0
2
(2%)
0
0
1
(1%)
1
(1%)
To Normal or No Change
87 (100%)
83 (98%)
88 (99%)
88 (99%)
91 (99%)
93 (97%)
To High
0
0
0
0
0
1
(1%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
87
0
85
2
0
87
0
87 (100%)
0
0
(98%)
(2%)
85
0
84
1
0
85
1
80
4
0
(99%)
(1%)
(1%)
(94%)
(5%)
89
0
87
1
1
89
0
86
2
1
(98%)
(1%)
(1%)
89
1
85
2
1
(97%)
(2%)
(1%)
89
0
88
0
1
(1%)
(96%)
(2%)
(1%)
(99%)
(1%)
92
1
90
1
0
92
0
90
2
0
(1%)
(98%)
(1%)
(98%)
(2%)
96
0
94
1
1
(98%)
(1%)
(1%)
96
1
92
2
1
(1%)
(96%)
(2%)
(1%)
YM2008/00019/00
B2C109575
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
CONFIDENTIAL
549
Urea (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Basophils (GI/L)
Placebo
102 Screening
90
0.025
0.0197
0.020
0.00
0.10
Day 14
78
0.028
0.0220
0.020
0.00
0.11
Day 28
76
0.027
0.0284
0.020
0.00
0.20
Screening
Day 14
Day 28
85
79
80
0.021
0.022
0.026
0.0148
0.0150
0.0199
0.020
0.020
0.030
0.00
0.00
0.00
0.07
0.06
0.12
6.25mcg
101
Screening
Day 14
Day 28
86
76
80
0.023
0.024
0.025
0.0174
0.0183
0.0194
0.020
0.020
0.020
0.00
0.00
0.00
0.10
0.10
0.10
12.5mcg
100
Screening
Day 14
Day 28
83
73
76
0.025
0.023
0.023
0.0171
0.0189
0.0196
0.020
0.020
0.020
0.00
0.00
0.00
0.08
0.10
0.15
25mcg
101
Screening
Day 14
Day 28
87
78
78
0.025
0.025
0.025
0.0166
0.0202
0.0196
0.020
0.020
0.020
0.00
0.00
0.00
0.10
0.11
0.10
50mcg
102
Screening
Day 14
Day 28
81
74
81
0.024
0.022
0.024
0.0193
0.0175
0.0189
0.020
0.020
0.020
0.00
0.00
0.00
0.10
0.10
0.09
CONFIDENTIAL
101
550
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Eosinophils (GI/L) Placebo
102 Screening
99
0.276
0.2285
0.210
0.00
1.35
Day 14
87
0.294
0.1991
0.250
0.01
1.00
Day 28
84
0.303
0.2480
0.220
0.00
1.28
Screening
Day 14
Day 28
93
84
85
0.307
0.290
0.273
0.2378
0.2018
0.2222
0.250
0.240
0.220
0.00
0.00
0.00
1.70
1.17
1.40
6.25mcg
101
Screening
Day 14
Day 28
91
83
86
0.305
0.329
0.311
0.2242
0.2628
0.2610
0.220
0.260
0.230
0.00
0.04
0.01
0.94
1.10
1.40
12.5mcg
100
Screening
Day 14
Day 28
93
81
83
0.304
0.284
0.267
0.2490
0.2246
0.2216
0.240
0.210
0.220
0.03
0.00
0.02
1.66
1.40
1.33
25mcg
101
Screening
Day 14
Day 28
98
90
90
0.323
0.312
0.334
0.1954
0.2060
0.2358
0.285
0.245
0.280
0.00
0.04
0.00
0.98
0.98
1.06
50mcg
102
Screening
Day 14
Day 28
96
88
95
0.304
0.306
0.341
0.2504
0.3185
0.3321
0.230
0.220
0.240
0.00
0.00
0.00
2.00
2.40
2.70
CONFIDENTIAL
101
551
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Hematocrit (1)
Placebo
102 Screening
99
0.4237
0.03535
0.4230
0.352
0.529
Day 14
87
0.4094
0.03476
0.4140
0.325
0.480
Day 28
85
0.4085
0.03297
0.4140
0.336
0.478
Screening
Day 14
Day 28
93
84
85
0.4298
0.4114
0.4128
0.04413
0.03262
0.03292
0.4260
0.4125
0.4110
0.325
0.325
0.327
0.654
0.482
0.496
6.25mcg
101
Screening
Day 14
Day 28
91
84
86
0.4315
0.4136
0.4129
0.04201
0.04301
0.04264
0.4340
0.4200
0.4125
0.290
0.267
0.258
0.546
0.487
0.484
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
0.4219
0.4042
0.4063
0.04692
0.03882
0.04340
0.4220
0.4110
0.4075
0.232
0.279
0.264
0.526
0.467
0.490
25mcg
101
Screening
Day 14
Day 28
98
90
90
0.4242
0.4046
0.4089
0.03643
0.03609
0.03670
0.4250
0.4040
0.4105
0.320
0.286
0.296
0.507
0.484
0.495
50mcg
102
Screening
Day 14
Day 28
96
89
95
0.4175
0.4044
0.4073
0.04566
0.04245
0.03791
0.4185
0.4050
0.4060
0.215
0.269
0.308
0.542
0.527
0.483
CONFIDENTIAL
101
552
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Hemoglobin (G/L)
Placebo
102 Screening
99 140.0
12.15
139.0
114
173
Day 14
87 134.1
12.03
134.0
103
161
Day 28
85 134.2
11.54
134.0
107
162
Screening
Day 14
Day 28
93
84
85
141.7
135.0
135.1
14.16
11.56
10.83
141.0
135.0
134.0
104
103
106
211
164
162
6.25mcg
101
Screening
Day 14
Day 28
91
84
86
141.8
136.0
135.2
14.25
15.74
15.29
144.0
138.5
137.0
92
85
80
167
164
161
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
139.4
132.1
132.8
16.75
14.14
15.79
141.0
134.0
132.5
66
80
74
174
152
160
25mcg
101
Screening
Day 14
Day 28
98
90
90
139.7
132.9
133.6
12.47
12.34
12.37
141.0
133.0
134.0
96
89
91
165
163
162
50mcg
102
Screening
Day 14
Day 28
96
89
95
137.4
132.0
133.4
16.36
14.03
13.49
138.5
132.0
133.0
59
85
94
168
164
160
CONFIDENTIAL
101
553
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Lymphocytes (GI/L) Placebo
102 Screening
99
2.607
0.8562
2.520
0.82
6.10
Day 14
87
2.392
0.7292
2.290
1.16
4.38
Day 28
84
2.447
0.7643
2.330
1.25
5.20
Screening
Day 14
Day 28
93
84
85
2.615
2.343
2.345
0.8272
0.6532
0.6458
2.470
2.315
2.250
1.06
1.16
1.00
5.50
4.10
4.27
6.25mcg
101
Screening
Day 14
Day 28
91
83
86
2.394
2.238
2.227
0.6557
0.6371
0.6261
2.320
2.140
2.160
1.13
1.22
1.07
4.80
3.99
4.13
12.5mcg
100
Screening
Day 14
Day 28
93
81
83
2.478
2.306
2.316
0.6898
0.7392
0.8288
2.420
2.150
2.110
1.22
1.05
0.85
4.52
5.20
6.22
25mcg
101
Screening
Day 14
Day 28
98
90
90
2.637
2.390
2.334
0.8179
0.6790
0.7443
2.420
2.300
2.230
0.97
1.25
1.22
5.60
5.00
4.91
50mcg
102
Screening
Day 14
Day 28
96
88
95
2.528
2.419
2.261
0.8088
0.8334
0.6653
2.480
2.255
2.140
0.89
1.09
0.99
5.10
6.57
4.28
CONFIDENTIAL
101
554
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99
29.95
1.927
30.00
21.8
33.7
Hemoglobin (PG)
Day 14
87
30.17
1.738
30.00
23.9
33.8
Day 28
85
30.17
1.911
30.20
22.6
33.8
101
Screening
Day 14
Day 28
93
84
85
30.50
30.52
30.52
1.607
1.617
1.508
30.60
30.60
30.60
25.1
25.4
25.6
34.7
35.3
33.4
6.25mcg
101
Screening
Day 14
Day 28
91
84
86
30.05
29.99
30.02
2.368
2.539
2.489
30.20
30.30
30.15
20.9
20.9
20.9
39.9
40.1
40.1
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
29.98
29.67
29.68
2.218
2.243
2.243
30.10
29.80
29.80
19.2
20.2
20.2
34.0
34.0
33.8
25mcg
101
Screening
Day 14
Day 28
98
90
90
29.86
29.84
29.71
1.767
1.976
1.927
29.90
30.00
29.80
22.6
22.6
22.6
34.4
34.3
34.1
50mcg
102
Screening
Day 14
Day 28
96
89
95
29.93
29.97
29.91
2.965
2.270
2.642
30.50
30.10
30.40
16.4
20.9
18.5
34.6
33.9
34.7
CONFIDENTIAL
555
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99 330.1
10.57
328.0
306
354
Hemoglobin
concentration
(G/L)
Day 14
87 327.5
9.00
327.0
306
354
Day 28
85 327.8
9.71
329.0
306
355
Screening
Day 14
Day 28
93
84
85
330.0
328.0
327.8
10.19
9.88
8.80
328.0
327.5
326.0
306
306
306
354
350
345
6.25mcg
101
Screening
Day 14
Day 28
91
84
86
328.4
328.2
326.9
10.51
9.38
10.75
328.0
329.0
327.0
306
298
303
353
348
353
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
330.5
326.9
326.7
10.54
10.73
10.81
331.0
327.0
327.0
286
288
281
354
352
354
25mcg
101
Screening
Day 14
Day 28
98
90
90
329.3
328.1
326.8
9.89
10.38
9.96
330.0
329.0
325.5
299
290
290
351
352
354
50mcg
102
Screening
Day 14
Day 28
96
89
95
328.5
326.4
326.9
11.86
10.81
9.85
331.0
325.0
327.0
270
294
306
349
354
350
YM2008/00019/00
B2C109575
101
CONFIDENTIAL
556
3mcg
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99
90.7
5.26
90.0
70
103
Volume (FL)
Day 14
87
92.1
4.99
92.0
76
105
Day 28
85
91.8
5.26
92.0
71
103
101
Screening
Day 14
Day 28
93
84
85
92.5
93.2
93.3
4.70
5.00
4.55
92.0
93.0
93.0
79
80
80
107
110
104
6.25mcg
101
Screening
Day 14
Day 28
91
84
85
91.4
91.3
91.8
6.23
6.75
6.60
91.0
91.0
91.0
70
69
68
122
122
121
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
90.7
90.9
90.9
5.79
6.10
5.71
91.0
91.0
91.0
67
70
72
104
106
101
25mcg
101
Screening
Day 14
Day 28
98
90
90
90.7
91.0
90.9
4.79
5.54
5.60
90.0
91.0
91.0
75
74
74
103
106
108
50mcg
102
Screening
Day 14
Day 28
96
89
95
91.0
91.9
91.3
7.58
6.50
7.01
92.0
92.0
92.0
60
67
61
103
106
106
CONFIDENTIAL
557
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Monocytes (GI/L)
Placebo
102 Screening
99
0.395
0.1834
0.380
0.00
0.92
Day 14
87
0.364
0.1903
0.330
0.00
0.91
Day 28
84
0.367
0.1943
0.315
0.01
1.11
Screening
Day 14
Day 28
93
84
85
0.397
0.352
0.366
0.1766
0.1688
0.2185
0.390
0.315
0.340
0.05
0.00
0.01
0.93
0.84
1.62
6.25mcg
101
Screening
Day 14
Day 28
91
83
86
0.395
0.344
0.345
0.1704
0.1637
0.1840
0.390
0.320
0.305
0.01
0.06
0.04
0.87
0.78
0.95
12.5mcg
100
Screening
Day 14
Day 28
93
81
83
0.376
0.335
0.338
0.1731
0.1336
0.1487
0.360
0.320
0.300
0.00
0.00
0.08
1.16
0.62
0.79
25mcg
101
Screening
Day 14
Day 28
98
90
90
0.399
0.395
0.358
0.1852
0.2011
0.1521
0.360
0.355
0.340
0.02
0.10
0.05
0.94
1.18
0.96
50mcg
102
Screening
Day 14
Day 28
96
88
95
0.386
0.371
0.348
0.1681
0.2191
0.1587
0.370
0.350
0.330
0.02
0.01
0.02
0.84
1.46
0.76
CONFIDENTIAL
101
558
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Platelet count
Placebo
102 Screening
98 275.3
66.55
264.5
159
541
(GI/L)
Day 14
87 270.7
61.61
268.0
154
457
Day 28
82 278.1
71.95
270.0
95
496
101
Screening
Day 14
Day 28
93
82
84
271.6
269.2
264.7
60.97
58.80
61.58
262.0
265.5
258.0
96
144
135
437
464
467
6.25mcg
101
Screening
Day 14
Day 28
89
83
84
256.2
252.8
249.1
56.55
54.07
58.11
253.0
244.0
236.0
144
142
82
423
465
476
12.5mcg
100
Screening
Day 14
Day 28
93
79
83
264.9
269.5
267.0
51.26
60.97
58.16
263.0
268.0
259.0
139
75
145
370
400
426
25mcg
101
Screening
Day 14
Day 28
98
89
87
264.2
264.7
270.4
57.99
54.28
62.43
256.0
260.0
265.0
124
140
135
410
433
441
50mcg
102
Screening
Day 14
Day 28
93
87
93
282.6
272.0
272.0
71.22
64.48
58.61
281.0
271.0
268.0
115
140
151
501
503
471
CONFIDENTIAL
559
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Red Blood Cell
Placebo
102 Screening
99
4.69
0.452
4.70
3.6
6.3
count (TI/L)
Day 14
87
4.46
0.442
4.40
3.4
5.6
Day 28
85
4.47
0.449
4.50
3.5
6.2
101
Screening
Day 14
Day 28
93
84
85
4.66
4.43
4.43
0.468
0.353
0.351
4.60
4.40
4.40
3.6
3.7
3.8
7.1
5.3
5.3
6.25mcg
101
Screening
Day 14
Day 28
91
84
86
4.74
4.55
4.51
0.464
0.484
0.449
4.70
4.60
4.50
3.6
3.4
3.5
6.1
5.6
5.5
12.5mcg
100
Screening
Day 14
Day 28
93
81
84
4.65
4.46
4.47
0.474
0.424
0.443
4.70
4.50
4.50
3.4
3.4
3.6
5.6
5.2
5.4
25mcg
101
Screening
Day 14
Day 28
98
90
90
4.69
4.46
4.52
0.454
0.452
0.449
4.70
4.40
4.50
3.7
3.6
3.7
5.8
5.6
5.5
50mcg
102
Screening
Day 14
Day 28
96
89
95
4.61
4.42
4.48
0.495
0.545
0.464
4.60
4.40
4.40
3.3
3.0
3.3
6.9
6.8
6.5
CONFIDENTIAL
560
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Total Neutrophils
Placebo
102 Screening
99
4.871
1.8185
4.570
1.91
13.13
(GI/L)
Day 14
87
4.740
1.9558
3.970
0.80
11.53
Day 28
84
4.845
1.7052
4.680
1.65
9.92
101
Screening
Day 14
Day 28
93
84
85
4.591
4.583
4.615
1.5541
1.7221
1.5389
4.550
4.375
4.440
1.43
1.37
1.67
10.75
11.64
9.03
6.25mcg
101
Screening
Day 14
Day 28
91
83
86
4.544
4.148
4.373
1.3390
1.1722
1.2918
4.400
4.060
4.210
2.11
1.88
2.01
8.89
8.47
8.58
12.5mcg
100
Screening
Day 14
Day 28
93
81
83
4.641
4.521
4.586
1.5256
1.4377
1.6108
4.440
4.230
4.350
2.21
2.09
1.92
9.09
7.43
9.84
25mcg
101
Screening
Day 14
Day 28
98
90
90
4.597
4.569
4.546
1.4732
1.5842
1.5431
4.420
4.330
4.245
1.36
1.34
1.78
8.81
9.99
9.68
50mcg
102
Screening
Day 14
Day 28
96
88
95
4.798
4.742
4.565
1.7048
1.6168
1.6008
4.580
4.525
4.200
1.46
2.08
1.65
11.61
9.94
10.52
CONFIDENTIAL
561
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 13
Table 8.14
Summary of Haematology Data
Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------White Blood Cell
Placebo
102 Screening
99
8.18
2.215
7.90
3.7
16.9
count (GI/L)
Day 14
87
7.82
2.278
7.10
2.5
15.6
Day 28
84
8.00
2.095
7.55
3.5
13.6
101
Screening
Day 14
Day 28
93
84
85
7.94
7.59
7.63
1.893
1.961
1.921
7.80
7.40
7.40
3.8
3.5
4.0
13.4
13.6
12.7
6.25mcg
101
Screening
Day 14
Day 28
91
83
86
7.66
7.09
7.29
1.704
1.447
1.644
7.50
6.80
7.20
4.6
4.4
4.5
15.1
12.2
12.9
12.5mcg
100
Screening
Day 14
Day 28
93
81
83
7.82
7.47
7.53
1.893
1.785
2.048
7.60
7.40
7.10
4.1
4.4
3.8
12.8
13.2
16.8
25mcg
101
Screening
Day 14
Day 28
98
90
90
7.98
7.69
7.60
1.896
1.982
1.954
7.85
7.40
7.45
3.9
3.8
3.9
14.6
13.5
12.6
50mcg
102
Screening
Day 14
Day 28
96
88
95
8.05
7.87
7.54
2.134
2.054
2.038
7.70
7.60
7.10
3.0
4.4
3.4
15.5
14.0
14.8
CONFIDENTIAL
562
3mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
78
0
79
0
76
0
73
0
78
0
74
0
Day 28
n
High
76
0
80
0
80
0
76
0
78
0
81
0
89
92
91
88
87
85
High
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
CONFIDENTIAL
563
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
9
3
(10%)
(3%)
84
6
4
(7%)
(5%)
83
13
3
(16%)
(4%)
81
9
5
(11%)
(6%)
90
11
1
(12%)
(1%)
88
11
5
(13%)
(6%)
Day 28
n
High
Low
84
10
4
(12%)
(5%)
85
7
5
(8%)
(6%)
86
16
7
(19%)
(8%)
83
7
4
(8%)
(5%)
90
14
4
(16%)
(4%)
95
11
4
(12%)
(4%)
98
High
Low
15
5
98
(15%)
(5%)
9
7
99
(9%)
(7%)
20
9
97
(20%)
(9%)
(15%)
(7%)
21
5
100
(21%)
(5%)
14
9
(14%)
(9%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
15
7
99
CONFIDENTIAL
564
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
565
87
1
8
n
High
Low
85
0
8
98
High
Low
1
10
(1%)
(9%)
84
0
8
(9%)
85
0
11
(10%)
84
0
7
(8%)
81
0
12
(13%)
86
1
9
(1%)
(10%)
84
0
10
98
(1%)
(10%)
1
18
99
(1%)
(18%)
1
13
(15%)
90
0
8
(12%)
90
0
10
97
(1%)
(13%)
(1%)
(18%)
(11%)
95
0
17
(18%)
99
(13%)
0
12
100
(12%)
1
24
(1%)
(24%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
13
(9%)
89
1
16
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
566
87
0
11
n
High
Low
85
0
13
98
High
Low
0
17
(13%)
84
0
20
(15%)
85
0
18
(24%)
84
0
15
(21%)
86
0
20
98
(17%)
0
28
(18%)
81
0
18
(23%)
84
0
19
99
(29%)
0
23
(22%)
90
0
19
(23%)
90
0
18
97
(23%)
(25%)
(20%)
95
0
23
(24%)
99
(25%)
0
27
100
(27%)
0
31
(31%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
24
(21%)
89
0
22
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
3
0
(3%)
84
0
0
Day 28
n
High
Low
84
3
0
(4%)
85
1
0
98
High
Low
4
0
83
0
0
(1%)
98
(4%)
1
0
86
1
0
(1%)
99
(1%)
2
0
81
3
0
(4%)
90
1
0
(1%)
88
3
0
(3%)
83
3
0
(4%)
90
3
0
(3%)
95
1
0
(1%)
97
(2%)
(5%)
3
0
100
(3%)
5
1
(5%)
(1%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
5
0
99
CONFIDENTIAL
567
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
2
3
(2%)
(3%)
84
1
2
(1%)
(2%)
84
3
6
(4%)
(7%)
81
1
8
(1%)
(10%)
90
1
6
(1%)
(7%)
89
1
6
(1%)
(7%)
Day 28
n
High
Low
85
2
4
(2%)
(5%)
85
1
1
(1%)
(1%)
86
6
5
(7%)
(6%)
84
3
9
(4%)
(11%)
90
1
6
(1%)
(7%)
95
3
8
(3%)
(8%)
98
High
Low
3
5
98
(3%)
(5%)
2
2
99
(2%)
(2%)
6
8
97
(6%)
(8%)
(5%)
(9%)
1
6
100
(1%)
(6%)
3
9
(3%)
(9%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
5
9
99
CONFIDENTIAL
568
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
569
87
0
15
n
High
Low
85
0
12
98
High
Low
0
20
(17%)
84
0
13
(14%)
85
0
12
(15%)
84
0
10
(14%)
86
0
15
98
(20%)
0
19
(12%)
81
0
18
(17%)
84
0
16
99
(19%)
0
19
(22%)
90
0
15
(19%)
90
0
12
97
(19%)
(24%)
(13%)
95
0
13
(14%)
99
(27%)
0
20
100
(20%)
0
26
(26%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
26
(17%)
89
0
21
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
3
1
(3%)
(1%)
84
4
0
(5%)
84
3
4
(4%)
(5%)
81
3
3
(4%)
(4%)
90
4
3
(4%)
(3%)
89
5
3
(6%)
(3%)
Day 28
n
High
Low
85
2
2
(2%)
(2%)
85
5
0
(6%)
85
4
3
(5%)
(4%)
84
2
3
(2%)
(4%)
90
3
3
(3%)
(3%)
95
4
5
(4%)
(5%)
98
High
Low
3
2
98
(3%)
(2%)
8
0
99
(8%)
5
4
97
(5%)
(4%)
(4%)
(3%)
4
3
100
(4%)
(3%)
5
6
(5%)
(6%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
4
3
99
CONFIDENTIAL
570
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
571
87
0
13
n
High
Low
84
1
12
98
High
Low
1
20
(15%)
84
0
9
(11%)
83
0
15
(1%)
(14%)
85
1
16
(1%)
(19%)
86
0
17
98
(1%)
(20%)
1
20
(18%)
81
0
13
(20%)
83
0
14
99
(1%)
(20%)
0
28
(16%)
90
1
12
(17%)
90
0
10
97
(28%)
88
2
14
(2%)
(16%)
(11%)
95
0
15
(16%)
99
(24%)
1
21
100
(1%)
(21%)
3
24
(3%)
(24%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
23
(1%)
(13%)
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
3
0
Day 28
n
High
Low
82
5
1
98
High
Low
5
1
(3%)
(6%)
(1%)
82
2
0
(2%)
83
1
0
84
2
0
(2%)
84
1
1
98
(5%)
(1%)
3
1
(1%)
(1%)
(1%)
99
(3%)
(1%)
1
1
79
0
1
83
2
0
(1%)
(2%)
96
(1%)
(1%)
(3%)
87
4
0
(5%)
87
5
0
(6%)
93
3
0
(3%)
98
(2%)
(1%)
6
0
99
(6%)
5
0
(5%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
1
89
3
0
CONFIDENTIAL
572
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
573
87
1
8
(1%)
(9%)
84
0
8
n
High
Low
85
2
10
(2%)
(12%)
85
0
9
98
High
Low
2
13
(10%)
84
0
10
(11%)
86
0
14
98
(2%)
(13%)
0
15
(12%)
81
0
6
(16%)
84
0
10
99
(15%)
0
15
(7%)
90
2
8
(2%)
(9%)
89
1
11
(1%)
(12%)
(12%)
90
2
10
(2%)
(11%)
95
1
7
(1%)
(7%)
97
(15%)
(11%)
3
13
100
(3%)
(13%)
1
16
(1%)
(16%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
0
11
99
CONFIDENTIAL
Day 28
n
High
Low
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
9
1
(10%)
(1%)
84
3
2
(4%)
(2%)
83
1
0
(1%)
81
0
0
Day 28
n
High
Low
84
6
1
(7%)
(1%)
85
3
1
(4%)
(1%)
86
1
0
(1%)
83
1
0
98
High
Low
14
2
98
(14%)
(2%)
7
3
99
(7%)
(3%)
1
1
(1%)
97
(1%)
(1%)
(3%)
(1%)
88
4
0
90
3
1
(3%)
(1%)
95
3
1
99
(2%)
6
1
(5%)
(3%)
(1%)
100
(6%)
(1%)
7
1
(7%)
(1%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
2
0
90
3
1
CONFIDENTIAL
574
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range
87
8
1
(9%)
(1%)
84
4
1
Day 28
n
High
Low
84
8
1
(10%)
(1%)
85
7
0
98
High
Low
13
2
(5%)
(1%)
(8%)
98
(13%)
(2%)
11
1
83
1
0
(1%)
81
5
0
(6%)
90
6
0
(7%)
88
8
0
86
2
0
(2%)
83
3
0
(4%)
90
7
0
(8%)
95
5
2
99
(11%)
(1%)
3
0
97
(3%)
(7%)
11
0
(5%)
(2%)
100
(11%)
12
2
(12%)
(2%)
YM2008/00019/00
B2C109575
Note: Any visit post screening may also contain unscheduled visits
7
0
99
(9%)
CONFIDENTIAL
575
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Basophils (GI/L)
n
78
79
76
73
78
74
To Normal or No Change
75 (96%)
72 (91%)
69 (91%)
69 (95%)
76 (97%)
69 (93%)
To High
0
0
0
0
0
0
Missing
3
(4%)
7
(9%)
7
(9%)
4
(5%)
2
(3%)
5
(7%)
(1%)
(91%)
(5%)
(3%)
84
2
72
3
7
Hematocrit (1)
n
To Low
To Normal or No Change
To High
Missing
87
7
76
1
3
(8%)
(87%)
(1%)
(3%)
84
4
73
0
7
Hemoglobin (G/L)
n
To Low
To Normal or No Change
To High
Missing
87
6
78
0
3
(7%)
(90%)
(3%)
84
10
67
0
7
(2%)
(86%)
(4%)
(8%)
(5%)
(87%)
(8%)
(12%)
(80%)
(8%)
83
1
67
6
9
84
1
74
0
9
84
4
71
0
9
(1%)
(81%)
(7%)
(11%)
(1%)
(88%)
(11%)
(5%)
(85%)
(11%)
81
4
69
4
4
81
6
71
0
4
81
10
67
0
4
(5%)
(85%)
(5%)
(5%)
(7%)
(88%)
(5%)
(12%)
(83%)
(5%)
90
1
81
6
2
90
6
82
0
2
90
15
73
0
2
(1%)
(90%)
(7%)
(2%)
(7%)
(91%)
(2%)
(17%)
(81%)
(2%)
88
4
73
6
5
89
10
74
0
5
89
11
73
0
5
(5%)
(83%)
(7%)
(6%)
(11%)
(83%)
(6%)
(12%)
(82%)
(6%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
1
79
4
3
CONFIDENTIAL
576
Eosinophils (GI/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lymphocytes (GI/L)
n
87
84
83
81
90
88
To Low
0
0
0
0
0
0
To Normal or No Change
83 (95%)
77 (92%)
74 (89%)
76 (94%)
88 (98%)
81 (92%)
To High
1
(1%)
0
0
1
(1%)
0
2
(2%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)
87
11
73
0
3
87
0
82
2
3
(2%)
(92%)
(2%)
(3%)
84
0
77
0
7
(3%)
84
6
71
0
7
(94%)
(2%)
(3%)
84
0
76
1
7
(13%)
(84%)
(92%)
(8%)
84
1
74
0
9
(8%)
84
2
73
0
9
(90%)
(1%)
(8%)
84
0
75
0
9
(7%)
(85%)
(1%)
(88%)
(11%)
(2%)
(87%)
(11%)
(89%)
(11%)
81
0
77
0
4
81
11
66
0
4
81
1
75
1
4
(95%)
(5%)
90
0
88
0
2
(5%)
90
8
80
0
2
(1%)
(93%)
(1%)
(5%)
90
0
85
3
2
(14%)
(81%)
(98%)
(2%)
89
0
84
0
5
(2%)
89
12
72
0
5
(94%)
(3%)
(2%)
89
0
81
3
5
(9%)
(89%)
(94%)
(6%)
(13%)
(81%)
(6%)
(91%)
(3%)
(6%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
2
80
2
3
CONFIDENTIAL
577
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Monocytes (GI/L)
n
87
84
83
81
90
88
To Low
10 (11%)
7
(8%)
9 (11%)
10 (12%)
10 (11%)
11 (13%)
To Normal or No Change
74 (85%)
70 (83%)
65 (78%)
67 (83%)
77 (86%)
70 (80%)
To High
0
0
0
0
1
(1%)
2
(2%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)
87
5
79
0
3
87
1
77
6
3
(95%)
(5%)
82
0
75
0
7
(3%)
84
5
72
0
7
(1%)
(89%)
(7%)
(3%)
84
1
75
1
7
(6%)
(91%)
(91%)
(9%)
83
0
73
0
10
(8%)
84
7
68
0
9
(1%)
(89%)
(1%)
(8%)
83
0
74
0
9
(6%)
(86%)
(88%)
(12%)
(8%)
(81%)
(11%)
(89%)
(11%)
79
1
74
0
4
81
1
76
0
4
81
0
77
0
4
(1%)
(94%)
(5%)
(1%)
(94%)
(5%)
(95%)
(5%)
89
0
87
0
2
90
6
82
0
2
90
0
85
3
2
(98%)
(2%)
88
0
79
1
8
(2%)
89
8
76
0
5
(94%)
(3%)
(2%)
88
0
80
3
5
(7%)
(91%)
(90%)
(1%)
(9%)
(9%)
(85%)
(6%)
(91%)
(3%)
(6%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
87
0
83
0
4
CONFIDENTIAL
578
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------White Blood Cell count (GI/L)
n
87
84
83
81
90
88
To Low
1
(1%)
1
(1%)
0
0
0
0
To Normal or No Change
80 (92%)
76 (90%)
74 (89%)
76 (94%)
84 (93%)
78 (89%)
To High
3
(3%)
0
0
1
(1%)
4
(4%)
5
(6%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)
CONFIDENTIAL
579
YM2008/00019/00
B2C109575
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Basophils (GI/L)
n
76
80
80
76
78
81
To Normal or No Change
73 (96%)
72 (90%)
73 (91%)
70 (92%)
77 (99%)
77 (95%)
To High
0
0
0
0
0
0
Missing
3
(4%)
8 (10%)
7
(9%)
6
(8%)
1
(1%)
4
(5%)
Hematocrit (1)
n
To Low
To Normal or No Change
To High
Missing
85
7
75
0
3
Hemoglobin (G/L)
n
To Low
To Normal or No Change
To High
Missing
85
9
73
0
3
(1%)
(90%)
(5%)
(4%)
(8%)
(88%)
(4%)
(11%)
(86%)
(4%)
85
3
70
4
8
85
8
69
0
8
85
12
65
0
8
(4%)
(82%)
(5%)
(9%)
(9%)
(81%)
(9%)
(14%)
(76%)
(9%)
86
1
68
8
9
86
7
70
0
9
86
9
68
0
9
(1%)
(79%)
(9%)
(10%)
(8%)
(81%)
(10%)
(10%)
(79%)
(10%)
83
3
71
3
6
84
5
73
0
6
84
12
66
0
6
(4%)
(86%)
(4%)
(7%)
(6%)
(87%)
(7%)
(14%)
(79%)
(7%)
90
2
80
7
1
90
8
81
0
1
90
16
73
0
1
(2%)
(89%)
(8%)
(1%)
(9%)
(90%)
(1%)
(18%)
(81%)
(1%)
95
4
80
7
4
95
8
83
0
4
95
9
82
0
4
(4%)
(84%)
(7%)
(4%)
(8%)
(87%)
(4%)
(9%)
(86%)
(4%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
84
1
76
4
3
CONFIDENTIAL
580
Eosinophils (GI/L)
n
To Low
To Normal or No Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lymphocytes (GI/L)
n
84
85
86
83
90
95
To Low
0
0
0
0
0
0
To Normal or No Change
81 (96%)
76 (89%)
76 (88%)
76 (92%)
88 (98%)
90 (95%)
To High
0
1
(1%)
1
(1%)
1
(1%)
1
(1%)
1
(1%)
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)
85
7
75
0
3
85
0
81
1
3
(1%)
(93%)
(2%)
(4%)
85
0
76
1
8
(4%)
85
7
70
0
8
(95%)
(1%)
(4%)
85
0
74
3
8
(8%)
(88%)
(89%)
(1%)
(9%)
86
0
75
2
9
(9%)
86
5
72
0
9
(87%)
(4%)
(9%)
85
0
75
1
9
(8%)
(82%)
(87%)
(2%)
(10%)
84
1
75
2
6
(10%)
84
8
70
0
6
(88%)
(1%)
(11%)
84
1
76
1
6
(6%)
(84%)
(1%)
(89%)
(2%)
(7%)
90
0
89
0
1
(7%)
90
5
84
0
1
(1%)
(90%)
(1%)
(7%)
90
0
87
2
1
(10%)
(83%)
(99%)
(1%)
95
0
91
0
4
(1%)
95
4
87
0
4
(97%)
(2%)
(1%)
95
0
89
2
4
(6%)
(93%)
(96%)
(4%)
(4%)
(92%)
(4%)
(94%)
(2%)
(4%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
85
1
79
2
3
CONFIDENTIAL
581
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Monocytes (GI/L)
n
84
85
86
83
90
95
To Low
9 (11%)
10 (12%)
11 (13%)
12 (14%)
9 (10%)
13 (14%)
To Normal or No Change
72 (86%)
66 (78%)
66 (77%)
65 (78%)
80 (89%)
78 (82%)
To High
0
1
(1%)
0
0
0
0
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)
85
7
75
0
3
84
1
74
6
3
(93%)
(2%)
(5%)
84
0
75
1
8
(4%)
85
7
70
0
8
(1%)
(88%)
(7%)
(4%)
85
1
74
2
8
(8%)
(88%)
(89%)
(1%)
(10%)
84
0
74
0
10
(9%)
86
10
67
0
9
(1%)
(87%)
(2%)
(9%)
86
0
77
0
9
(8%)
(82%)
(88%)
(12%)
(12%)
(78%)
(10%)
(90%)
(10%)
83
0
75
2
6
84
4
74
0
6
83
0
76
1
6
87
0
85
1
1
(98%)
(1%)
(1%)
93
0
87
0
6
(7%)
90
7
81
1
1
(8%)
(90%)
(1%)
(1%)
95
3
88
0
4
(92%)
(1%)
(7%)
90
0
86
3
1
(96%)
(3%)
(1%)
95
1
88
2
4
(90%)
(2%)
(7%)
(5%)
(88%)
(94%)
(6%)
(3%)
(93%)
(4%)
(1%)
(93%)
(2%)
(4%)
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
YM2008/00019/00
B2C109575
82
0
76
2
4
CONFIDENTIAL
582
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 8
Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range
Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------White Blood Cell count (GI/L)
n
84
85
86
83
90
95
To Low
0
0
0
0
0
1
(1%)
To Normal or No Change
77 (92%)
74 (87%)
76 (88%)
76 (92%)
84 (93%)
88 (93%)
To High
4
(5%)
3
(4%)
1
(1%)
1
(1%)
5
(6%)
2
(2%)
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)
CONFIDENTIAL
583
YM2008/00019/00
B2C109575
Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.17
Summary of Urine Dipstick Results
Visit: Screening
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Glucose
n
101
96
97
95
95
99
(dipstick)
TRACE
1 (<1%)
1
(1%)
0
1
(1%)
0
0
2+
0
0
0
0
1
(1%)
0
3+
1 (<1%)
1
(1%)
0
1
(1%)
0
2
(2%)
NEGATIVE
99 (98%)
94 (98%)
97 (100%)
93 (98%)
94 (99%)
97 (98%)
584
Urine Protein
(dipstick)
n
TRACE
1+
2+
NEGATIVE
n
TRACE
1+
2+
3+
NEGATIVE
101
4
2
1
94
96
(4%)
(2%)
(<1%)
(93%)
101
9
10
2
0
80
5
1
0
90
97
(5%)
(1%)
(94%)
96
(9%)
(10%)
(2%)
(79%)
8
5
0
1
82
3
0
1
93
95
(3%)
(1%)
(96%)
97
(8%)
(5%)
(1%)
(85%)
6
1
0
0
90
3
1
0
91
95
(3%)
(1%)
(96%)
95
(6%)
(1%)
(93%)
7
3
1
0
84
1
0
0
94
99
(1%)
(99%)
95
(7%)
(3%)
(1%)
(88%)
5
5
1
0
84
3
0
0
96
(3%)
(97%)
99
(5%)
(5%)
(1%)
(88%)
8
7
0
0
84
(8%)
(7%)
CONFIDENTIAL
Urine Ketones
(dipstick)
(85%)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.17
Summary of Urine Dipstick Results
Visit: Screening
585
Urine pH
n
Mean
SD
Median
Min.
Max.
101
5.94
0.392
6.00
5.5
7.5
96
6.04
0.392
6.00
5.0
7.5
97
6.02
0.448
6.00
5.5
7.0
95
6.04
0.474
6.00
5.5
7.5
95
5.92
0.429
6.00
5.5
7.5
99
6.03
0.459
6.00
5.5
7.5
Urine Specific
Gravity
101
96
97
95
95
99
1.0219
0.00806
1.0230
1.006
1.039
1.0225
0.00716
1.0230
1.007
1.043
1.0215
0.00758
1.0220
1.005
1.038
1.0226
0.00744
1.0230
1.007
1.039
1.0245
0.02942
1.0220
1.006
1.300
1.0512
0.30049
1.0220
1.006
4.010
YM2008/00019/00
B2C109575
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Leukocyte
n
101
96
97
95
95
99
Esterase test for
detecting WBC
(dipstick)
MODERATE
1 (<1%)
0
0
0
0
1
(1%)
TRACE
4
(4%)
5
(5%)
3
(3%)
1
(1%)
6
(6%)
6
(6%)
1+
6
(6%)
3
(3%)
2
(2%)
4
(4%)
5
(5%)
7
(7%)
2+
3
(3%)
1
(1%)
1
(1%)
3
(3%)
4
(4%)
0
3+
1 (<1%)
1
(1%)
1
(1%)
0
0
0
NEGATIVE
86 (85%)
86 (90%)
90 (93%)
87 (92%)
80 (84%)
85 (86%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.17
Summary of Urine Dipstick Results
Visit: Day 28
Urine Ketones
(dipstick)
586
Urine Protein
(dipstick)
85
TRACE
1+
NEGATIVE
4
2
79
85
TRACE
1+
2+
3+
NEGATIVE
10
7
1
0
67
85
(5%)
(2%)
(93%)
2
1
82
86
(2%)
(1%)
(96%)
85
(12%)
(8%)
(1%)
(79%)
7
3
0
1
74
1
0
85
85
(1%)
(99%)
86
(8%)
(4%)
(1%)
(87%)
6
3
0
1
76
4
0
81
90
(5%)
(95%)
85
(7%)
(3%)
(1%)
(88%)
5
5
1
0
74
2
0
88
95
(2%)
(98%)
90
(6%)
(6%)
(1%)
(87%)
9
2
1
0
78
0
0
95 (100%)
95
(10%)
(2%)
(1%)
(87%)
11
4
0
1
79
CONFIDENTIAL
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Glucose
n
85
85
86
85
90
95
(dipstick)
TRACE
1
(1%)
0
1
(1%)
0
1
(1%)
0
1+
0
0
0
0
0
1
(1%)
2+
0
0
1
(1%)
2
(2%)
0
0
3+
0
1
(1%)
0
0
1
(1%)
1
(1%)
4+
0
0
0
0
0
1
(1%)
NEGATIVE
84 (99%)
84 (99%)
84 (98%)
83 (98%)
88 (98%)
92 (97%)
(12%)
(4%)
(1%)
(83%)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.17
Summary of Urine Dipstick Results
Visit: Day 28
587
Urine pH
n
Mean
SD
Median
Min.
Max.
85
6.00
0.415
6.00
5.5
7.0
85
6.05
0.408
6.00
5.0
8.0
86
6.08
0.534
6.00
5.5
8.5
85
6.00
0.408
6.00
5.0
7.0
90
5.86
0.361
6.00
5.0
7.0
95
6.08
0.544
6.00
5.0
8.5
Urine Specific
Gravity
85
85
86
85
90
95
1.0213
0.00821
1.0210
1.005
1.042
1.0227
0.00714
1.0220
1.008
1.048
1.0211
0.00762
1.0230
1.001
1.038
1.0223
0.00753
1.0230
1.006
1.042
1.0224
0.00767
1.0230
1.006
1.040
1.0221
0.00681
1.0240
1.005
1.035
YM2008/00019/00
B2C109575
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Leukocyte
n
85
85
86
85
90
95
Esterase test for
detecting WBC
(dipstick)
SMALL
0
0
1
(1%)
0
0
2
(2%)
MODERATE
0
0
0
0
1
(1%)
0
TRACE
2
(2%)
3
(4%)
2
(2%)
4
(5%)
5
(6%)
6
(6%)
1+
1
(1%)
2
(2%)
1
(1%)
3
(4%)
9 (10%)
4
(4%)
2+
3
(4%)
3
(4%)
2
(2%)
1
(1%)
4
(4%)
0
3+
0
2
(2%)
1
(1%)
2
(2%)
2
(2%)
0
NEGATIVE
79 (93%)
75 (88%)
79 (92%)
75 (88%)
69 (77%)
83 (87%)
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
Placebo
102 Screening
102 124.1 13.26 124.0
90
150
102
102
102
102
102
123.3
123.6
124.2
124.4
124.4
15.42
14.65
15.20
15.01
15.46
121.0
122.0
124.0
122.0
125.5
90
92
85
92
90
159
158
158
159
160
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
122.6
122.3
123.1
123.4
123.1
14.70
14.30
15.58
15.59
14.68
122.0
122.0
122.0
123.0
121.0
90
92
88
88
88
152
163
159
163
160
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
123.2
122.3
123.3
123.5
123.8
15.03
14.67
14.50
16.00
14.34
121.0
121.5
121.0
120.5
122.0
90
90
96
88
96
155
161
153
156
165
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
122.6
123.0
122.9
123.0
125.1
14.66
15.37
14.17
15.15
15.34
122.5
122.0
122.0
123.0
126.0
88
86
92
90
92
155
166
164
161
174
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
588
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
3mcg
101 Screening
101 122.5 14.84 123.0
87
154
101
101
101
101
101
123.2
123.8
125.0
125.1
124.2
14.38
15.63
16.20
16.05
15.87
123.0
122.0
127.0
124.0
124.0
90
90
88
90
90
160
165
172
165
159
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
122.7
122.6
123.1
124.0
124.4
14.38
15.03
15.50
15.43
13.80
121.0
122.0
123.0
126.0
124.0
92
84
86
87
90
160
167
180
172
150
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
122.1
121.9
121.3
121.5
122.7
13.98
13.31
14.13
14.46
14.15
124.0
122.0
120.0
122.5
123.5
90
95
83
85
90
155
162
159
155
158
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
121.5
121.2
122.4
122.9
122.8
14.73
14.36
13.41
15.30
13.89
122.0
120.0
122.0
121.0
120.0
88
90
92
90
89
157
166
158
168
164
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
589
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
6.25mcg
101 Screening
101 124.7 13.83 123.0
90
159
101
101
101
101
101
123.9
123.6
124.0
125.3
124.9
13.95
13.57
14.41
14.09
13.83
123.0
124.0
122.0
124.0
125.0
98
92
98
98
99
175
171
167
162
170
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
97
97
97
97
121.3
120.8
121.9
122.2
122.4
11.88
13.19
13.58
12.85
13.85
120.0
120.0
120.0
120.0
120.0
91
91
96
93
91
148
151
155
150
163
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
121.1
121.2
122.1
122.5
122.8
12.30
12.72
13.41
14.10
14.58
122.0
120.0
120.0
120.0
122.0
94
97
94
85
91
149
149
152
160
170
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
122.3
120.4
121.3
122.0
123.2
13.05
12.40
12.72
11.82
13.92
122.0
120.0
120.0
122.0
125.0
94
96
97
100
98
155
150
161
145
163
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
590
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
12.5mcg
100 Screening
100 125.1 14.80 125.5
92
159
100
100
99
99
99
125.6
125.0
124.8
124.8
125.9
13.60
13.69
13.77
13.63
14.49
126.0
124.5
122.0
126.0
124.0
96
96
98
90
94
160
158
159
160
164
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
93
123.1
123.8
125.4
125.6
126.7
13.54
14.16
13.60
14.72
14.31
120.0
122.0
124.0
127.0
127.0
90
98
98
95
92
153
156
158
161
164
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
123.7
122.6
125.4
125.1
125.4
14.83
16.41
15.50
14.45
15.07
122.0
122.0
126.0
125.0
125.0
88
86
90
80
80
155
161
161
158
166
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
125.1
124.9
124.2
124.9
124.7
13.13
12.82
13.06
14.54
13.54
126.0
124.5
124.0
122.0
124.0
90
95
90
90
90
156
155
159
165
157
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
591
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
25mcg
101 Screening
101 121.9 13.42 122.0
90
153
101
101
101
101
101
123.6
123.8
124.1
123.6
123.8
12.62
14.07
14.21
13.57
14.44
125.0
122.0
122.0
122.0
122.0
98
90
94
95
95
153
160
160
156
170
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
95
96
96
96
122.9
121.8
122.1
123.6
123.7
14.16
14.31
15.00
14.46
13.63
122.0
120.0
120.0
120.0
122.5
86
100
94
98
90
155
150
151
158
153
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
120.8
121.7
123.1
122.1
122.6
15.02
14.89
14.94
14.44
13.51
122.0
121.0
120.5
124.0
124.0
86
88
96
88
96
146
150
152
150
150
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
122.8
121.8
121.6
122.8
122.7
13.15
14.15
14.04
14.36
13.48
121.5
120.0
120.0
122.0
120.0
90
97
88
95
95
165
153
149
152
152
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
592
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
50mcg
102 Screening
102 122.9 12.28 120.5
96
152
102
102
102
102
102
122.3
123.0
123.0
122.8
123.2
12.97
14.02
14.50
13.37
12.83
120.0
121.0
122.0
122.0
120.0
96
95
84
95
95
158
179
173
170
159
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
100
100
99
120.4
120.0
122.6
123.4
122.8
13.25
13.51
13.31
12.77
12.80
120.0
120.0
121.0
120.5
120.0
93
90
98
100
93
165
162
173
163
160
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
121.8
122.8
122.9
123.1
123.1
13.48
13.69
13.00
13.67
13.19
120.0
120.0
120.0
120.0
121.0
90
94
96
96
87
170
161
169
163
162
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
122.5
120.8
122.2
121.8
122.8
15.51
14.22
13.62
13.52
13.17
120.0
120.0
121.5
120.0
120.0
90
92
92
99
100
174
164
169
162
163
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
593
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
Placebo
102 Screening
102
77.9
9.37
78.0
56
99
102
102
102
102
102
77.3
78.4
77.9
79.2
79.2
9.59
10.13
10.55
10.03
10.55
78.0
78.5
78.0
80.0
80.0
52
54
50
54
56
96
97
102
100
100
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
76.9
76.3
76.2
76.7
76.5
10.57
9.58
9.77
9.49
9.91
76.0
76.0
75.0
77.0
77.0
52
57
58
54
50
98
96
97
94
100
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
77.2
77.2
77.4
76.5
76.7
10.17
10.29
9.94
10.28
10.12
77.0
78.0
80.0
78.0
78.0
51
52
58
50
40
98
98
98
97
98
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
77.3
76.8
77.7
77.4
77.5
10.23
9.48
9.78
10.35
11.13
76.0
78.0
77.0
78.0
78.0
57
54
54
52
46
100
96
100
100
101
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
594
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
3mcg
101 Screening
101
77.7
9.44
78.0
60
101
101
101
101
101
101
76.2
76.9
77.5
77.6
77.9
9.83
9.95
9.97
10.42
10.47
78.0
76.0
78.0
76.0
76.0
57
56
58
58
56
98
100
101
100
109
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
77.3
76.8
76.2
77.1
77.5
9.57
9.70
10.35
9.10
9.77
76.0
76.0
75.0
76.0
76.0
56
58
49
60
52
100
98
100
100
100
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
76.7
77.1
75.8
75.3
75.2
9.21
8.81
9.84
9.34
9.17
77.0
77.5
76.0
75.0
75.0
52
56
51
56
57
100
100
100
104
96
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
76.0
75.9
77.2
77.2
76.5
9.45
9.30
8.65
9.94
9.41
74.5
75.0
77.0
76.0
76.0
58
52
58
54
53
100
98
100
100
100
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
595
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
6.25mcg
101 Screening
101
78.1
8.05
80.0
60
96
101
101
101
101
101
77.2
78.0
76.8
78.1
77.5
8.55
8.79
8.66
7.89
8.92
78.0
79.0
76.0
80.0
78.0
60
54
58
60
58
99
100
95
96
100
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
97
97
97
97
75.9
76.1
77.0
76.0
76.4
8.93
8.70
9.29
9.60
9.19
76.0
78.0
78.0
76.0
78.0
56
55
53
52
51
95
98
107
105
109
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
75.2
75.8
76.4
76.0
76.8
8.38
8.54
9.32
9.63
9.33
74.0
76.0
77.0
75.0
76.0
55
53
59
54
52
96
97
105
103
104
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
77.6
75.7
76.3
77.2
78.5
8.51
9.24
8.51
8.60
7.58
78.0
75.0
76.0
78.0
79.0
58
53
57
45
60
94
98
96
97
96
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
596
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
12.5mcg
100 Screening
100
77.9
8.81
79.5
52
100
100
100
99
99
99
77.7
77.3
78.3
77.5
78.5
10.04
9.26
9.39
9.68
9.81
77.0
77.5
79.0
78.0
80.0
60
58
58
50
58
100
100
103
103
102
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
93
76.8
76.1
77.5
76.7
78.0
9.50
9.22
9.14
8.95
9.48
78.0
77.0
79.0
78.0
79.0
51
52
54
54
51
95
96
98
96
98
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
76.0
75.6
77.2
76.3
77.5
9.24
9.56
9.73
8.68
10.00
78.0
75.0
78.0
77.0
78.0
52
51
58
59
56
99
99
110
94
99
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
76.8
76.4
76.7
77.4
76.6
8.30
9.71
9.18
9.41
9.40
78.0
75.0
77.0
76.5
76.0
60
54
60
60
55
96
98
100
100
102
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
597
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
25mcg
101 Screening
101
76.2
9.85
78.0
58
100
101
101
101
101
101
76.6
77.8
77.3
78.0
78.4
9.20
9.26
9.15
9.19
9.14
77.0
78.0
77.0
78.0
78.0
50
59
60
60
60
96
98
98
100
99
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
95
96
96
96
75.8
75.8
76.4
75.8
76.6
9.08
9.67
10.24
9.30
9.59
76.0
76.0
76.0
76.0
77.0
54
57
54
55
53
96
96
97
98
95
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
76.0
75.1
76.2
75.8
75.4
9.85
10.18
10.13
10.73
10.10
76.0
74.5
76.5
75.0
76.0
47
55
49
43
58
95
100
98
100
99
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
76.4
75.1
76.1
76.8
76.2
10.00
9.68
10.20
10.60
9.85
77.0
75.0
75.0
77.0
74.0
58
52
54
56
48
98
99
100
107
99
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
598
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
50mcg
102 Screening
102
76.5
8.77
78.0
50
95
102
102
102
102
102
75.6
75.7
75.9
76.4
76.9
8.94
10.03
9.59
8.84
8.62
76.0
75.0
74.5
76.0
77.0
58
53
53
56
58
100
100
97
98
94
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
100
100
99
75.3
75.6
75.2
77.1
76.1
9.46
10.42
9.01
9.27
9.25
75.0
76.0
76.0
80.0
77.0
52
45
55
52
55
98
100
95
100
100
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
75.6
75.1
75.1
75.8
75.6
9.24
10.69
8.01
9.19
8.51
75.0
75.0
76.0
76.0
76.0
52
45
58
50
57
98
100
96
99
94
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
76.4
74.9
76.0
76.6
77.1
9.35
9.21
8.62
9.08
8.98
76.0
75.0
76.0
76.0
77.0
57
51
55
58
47
100
96
98
98
96
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
599
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) Placebo
102 Screening
102
75.6 10.64
76.0
50
107
102
102
102
102
102
72.8
71.6
69.6
70.6
70.7
9.74
10.44
11.18
10.89
10.21
73.0
72.0
71.0
71.0
72.0
47
51
40
38
40
94
96
99
99
99
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
74.0
72.6
71.8
72.3
72.9
9.90
9.52
9.88
10.17
8.98
72.0
72.0
72.0
72.0
72.0
54
54
51
51
57
104
100
96
96
97
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
74.5
72.6
72.0
72.7
73.9
10.96
8.65
9.01
9.83
9.43
73.0
72.0
71.0
72.0
74.0
53
56
53
48
55
102
100
94
100
98
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
73.7
71.4
71.1
69.8
70.8
10.18
9.40
9.38
9.31
9.03
72.0
70.0
70.0
70.0
72.0
54
54
52
49
52
115
96
92
95
91
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
600
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 3mcg
101 Screening
101
72.0
9.00
72.0
50
100
101
101
101
101
101
71.2
69.6
69.3
67.6
68.9
9.60
9.41
10.93
10.52
10.34
70.0
70.0
68.0
67.0
68.0
50
50
47
45
44
100
90
98
98
100
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
71.3
70.6
69.7
70.2
71.2
9.25
9.83
10.08
10.45
9.34
72.0
70.0
69.0
69.0
72.0
46
49
45
45
48
101
99
102
100
103
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
72.4
70.3
69.5
70.2
70.3
10.28
8.64
8.76
10.13
9.41
73.0
71.5
70.5
70.5
70.0
49
48
42
43
47
116
88
87
97
90
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
71.6
70.1
69.8
68.5
69.3
10.54
10.01
10.00
9.89
11.13
71.0
70.0
70.0
68.0
68.0
43
46
46
42
41
96
93
98
92
100
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
601
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 6.25mcg
101 Screening
101
72.3
9.03
71.0
55
110
101
101
101
101
101
70.7
70.1
68.4
67.7
68.3
9.12
8.47
9.05
9.01
9.33
70.0
70.0
69.0
67.0
68.0
54
52
48
48
47
89
88
87
88
89
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
97
97
97
97
72.3
72.4
70.0
69.9
69.9
10.38
9.77
9.80
9.22
8.41
72.0
72.0
71.0
70.0
70.0
51
53
46
51
50
97
94
97
95
92
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
72.7
72.2
70.0
69.9
70.3
11.91
8.75
8.56
8.52
9.31
72.0
72.0
70.0
70.0
71.0
52
51
51
50
54
112
90
89
89
94
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
72.4
70.8
69.2
68.6
67.8
10.19
9.93
9.79
9.95
9.92
72.0
70.0
69.0
68.0
68.0
52
53
50
51
42
99
94
92
93
94
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
602
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 12.5mcg
100 Screening
99
71.9
8.25
72.0
49
89
100
100
99
99
99
72.8
70.6
69.0
68.5
69.3
9.00
9.48
9.44
8.54
8.59
72.0
70.0
68.0
68.0
68.0
54
51
44
52
47
98
95
92
93
88
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
93
72.6
71.9
70.3
70.5
71.6
8.63
9.04
9.81
9.41
9.38
72.0
72.0
70.0
71.0
72.0
53
53
50
51
51
90
100
93
95
95
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
73.7
73.3
72.3
72.7
71.3
10.71
10.20
10.05
10.06
9.01
72.0
72.0
70.0
70.0
70.0
58
52
52
51
46
106
97
99
100
102
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
72.2
71.2
69.9
68.9
68.3
9.10
9.76
9.56
8.55
8.31
72.0
71.0
70.0
68.0
69.5
55
44
53
53
48
94
94
102
88
90
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
603
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 25mcg
101 Screening
101
71.9
9.53
72.0
50
90
101
101
101
101
101
72.6
72.6
70.7
69.2
70.1
9.76
10.21
10.22
9.12
9.68
72.0
74.0
72.0
69.0
72.0
47
47
48
45
48
102
98
94
91
89
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
95
96
96
96
74.2
73.5
71.9
71.1
71.9
10.34
9.81
9.37
9.08
9.76
74.0
74.0
71.5
71.0
72.0
50
49
50
50
47
100
92
90
92
90
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
74.3
74.2
72.2
72.9
72.5
10.66
10.32
10.63
10.44
10.01
74.0
72.0
71.5
72.5
72.0
47
52
54
50
50
100
101
103
101
98
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
73.6
73.1
71.6
70.3
69.6
10.17
9.43
10.72
10.32
9.95
73.0
73.0
72.0
69.0
69.0
46
50
48
48
46
95
102
104
99
90
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
604
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 18
Table 8.18
Summary of Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 50mcg
102 Screening
102
70.9
9.17
70.0
52
99
102
102
102
102
102
71.5
71.0
69.9
69.6
69.6
10.26
10.33
10.85
10.40
10.66
70.0
70.0
68.0
68.5
69.0
50
47
48
50
48
105
100
110
100
102
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
100
100
99
72.0
73.3
72.2
72.1
72.2
9.95
10.56
9.52
9.74
10.68
70.5
74.0
72.0
72.0
71.0
49
42
50
52
51
110
110
109
104
105
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
73.1
74.9
74.1
73.2
72.0
8.66
9.49
9.71
10.21
8.98
72.5
76.0
74.0
73.0
72.0
54
50
54
50
50
105
101
110
112
112
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
72.8
74.6
72.8
70.9
71.1
10.15
9.52
9.98
9.76
10.74
72.0
74.0
72.0
70.0
70.0
53
54
54
49
49
100
99
99
102
102
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
CONFIDENTIAL
605
Day 1
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
Placebo
102 Day 1
10 mins
102
0.4
9.56
0.0
-38
40
1 hour
102
0.9 10.70
2.0
-32
32
2 hours
102
1.2 12.02
1.0
-31
35
4 hours
102
1.1 12.13
0.0
-34
37
95
93
93
93
93
-1.1
-1.5
-0.8
-0.5
-0.8
12.25
12.28
13.52
12.95
10.73
0.0
0.0
0.0
0.0
0.0
-54
-30
-40
-40
-26
26
38
34
38
25
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
-0.7
-1.6
-0.7
-0.5
-0.1
12.49
12.20
12.61
12.76
12.92
-1.0
-0.5
0.0
0.0
0.0
-39
-44
-44
-46
-44
28
24
24
36
28
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
-1.3
-0.9
-1.0
-0.9
1.2
12.92
13.02
13.09
13.86
15.01
-0.5
-2.0
0.0
0.0
2.0
-33
-35
-28
-31
-31
32
41
39
36
49
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
606
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
3mcg
101 Day 1
10 mins
101
0.6
7.06
0.0
-16
19
1 hour
101
1.8
9.81
0.0
-21
37
2 hours
101
1.9 11.01
0.0
-24
32
4 hours
101
1.0 10.34
0.0
-20
35
95
93
93
93
93
-0.2
-0.8
-0.3
0.6
1.0
12.07
12.68
12.26
11.04
11.11
0.0
0.0
0.0
0.0
0.0
-26
-34
-28
-23
-23
26
35
32
33
35
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
-1.2
-1.1
-1.7
-1.5
-0.3
10.18
10.06
10.22
10.14
10.91
0.0
-1.5
-1.0
-2.0
0.0
-24
-20
-28
-33
-26
30
25
30
24
30
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
-1.5
-1.8
-0.5
-0.3
-0.3
11.71
11.26
11.43
11.70
10.88
0.0
-1.0
0.0
0.0
1.5
-24
-22
-20
-30
-23
25
31
35
33
27
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
607
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
6.25mcg
101 Day 1
10 mins
101 -0.3
8.86
0.0
-22
26
1 hour
101
0.0
8.74
0.0
-21
20
2 hours
101
1.4
9.70
0.0
-22
22
4 hours
101
1.0
8.61
0.0
-20
28
99
97
97
97
97
-2.4
-3.1
-2.0
-1.8
-1.5
11.01
11.63
12.69
11.47
11.90
0.0
-3.0
-1.0
-2.0
-2.0
-39
-39
-41
-36
-37
23
25
35
23
33
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
-3.0
-3.3
-2.4
-1.9
-1.7
10.63
10.92
10.66
11.49
12.14
-3.0
-4.0
-1.0
-3.0
-4.0
-28
-34
-29
-38
-30
21
25
24
32
45
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
-2.2
-4.1
-3.3
-2.5
-1.3
11.45
11.17
12.98
11.62
12.82
-2.0
-5.0
-5.0
-2.0
-3.0
-35
-45
-60
-44
-27
34
28
26
22
31
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
608
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
12.5mcg
100 Day 1
10 mins
100 -0.6
7.94
0.0
-30
18
1 hour
99 -0.7
9.63
0.0
-25
19
2 hours
99 -0.6
9.34
0.0
-24
25
4 hours
99
0.4
8.79
0.0
-22
34
97
96
95
95
93
-2.4
-1.8
-0.4
-0.1
1.2
8.87
9.78
11.24
10.31
10.68
0.0
0.0
0.0
0.0
0.0
-29
-27
-28
-26
-20
20
22
27
24
42
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
-1.6
-2.8
0.0
-0.3
0.0
11.17
12.58
12.25
11.91
11.16
0.0
-2.0
0.0
0.0
1.0
-35
-35
-45
-41
-35
21
22
27
31
26
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
-0.3
-0.5
-1.2
-0.5
-0.7
10.81
11.02
11.03
11.35
10.73
0.0
0.0
-1.0
0.0
-2.0
-24
-33
-31
-32
-28
35
30
32
35
40
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
609
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
25mcg
101 Day 1
10 mins
101
0.2
8.70
0.0
-35
23
1 hour
101
0.5
9.70
0.0
-25
36
2 hours
101
0.0
8.63
0.0
-34
26
4 hours
101
0.2
9.74
0.0
-33
46
97
95
96
96
96
-1.2
-2.2
-2.0
-0.5
-0.4
9.06
9.89
9.91
9.85
8.91
0.0
-2.0
0.0
0.0
0.0
-26
-32
-38
-30
-30
24
22
20
30
20
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
-3.1
-2.3
-0.9
-1.9
-1.4
10.64
10.47
11.34
10.73
10.36
-3.0
-3.0
0.0
-2.0
-2.0
-37
-26
-38
-33
-30
22
27
24
26
29
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
-1.2
-2.5
-2.6
-1.5
-1.6
10.68
11.05
10.91
10.87
10.80
0.0
0.0
-2.0
0.0
0.0
-30
-28
-25
-30
-35
29
26
28
22
22
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
610
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
50mcg
102 Day 1
10 mins
102
0.7
9.03
0.0
-34
39
1 hour
102
0.7
9.67
0.0
-36
33
2 hours
102
0.5
9.76
0.0
-26
31
4 hours
102
0.9
9.89
0.0
-27
23
100
100
100
100
99
-2.1
-2.4
0.2
0.9
0.3
11.04
10.63
10.99
10.69
10.44
-2.0
-2.0
0.0
0.0
0.0
-27
-25
-21
-36
-28
25
22
33
23
28
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
-0.6
0.3
0.6
0.7
0.8
9.79
11.19
10.68
12.27
10.84
0.0
0.0
0.0
0.0
0.0
-30
-32
-30
-29
-33
30
26
29
41
26
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
0.1
-1.6
-0.2
-0.6
0.4
11.11
12.09
11.54
11.89
10.73
0.0
0.0
0.0
0.0
0.0
-28
-41
-28
-32
-26
30
24
29
32
33
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
611
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
Placebo
102 Day 1
10 mins
102
1.2
6.07
1.0
-18
20
1 hour
102
0.6
7.67
0.0
-20
32
2 hours
102
1.9
7.25
1.0
-24
20
4 hours
102
1.9
8.55
0.5
-28
30
95
93
93
93
93
-0.3
-0.9
-1.0
-0.5
-0.7
8.46
8.41
8.69
8.39
7.75
-1.0
-1.0
-1.0
0.0
0.0
-24
-26
-28
-26
-28
22
23
24
21
20
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
0.0
0.2
0.5
-0.5
-0.2
10.13
9.69
9.46
9.50
9.71
0.0
0.0
0.5
-1.0
0.0
-25
-32
-24
-24
-24
42
24
30
24
23
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
0.5
0.0
0.9
0.6
0.7
8.46
8.24
9.35
8.96
9.47
0.0
0.0
1.0
0.0
0.0
-24
-20
-18
-19
-20
25
24
26
30
31
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
612
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
3mcg
101 Day 1
10 mins
101
0.7
6.23
0.0
-20
24
1 hour
101
1.3
7.30
0.0
-22
20
2 hours
101
1.4
7.58
1.0
-15
26
4 hours
101
1.7
8.85
2.0
-21
24
95
93
93
93
93
1.0
0.4
-0.2
0.7
1.1
8.17
8.05
8.24
7.56
7.66
0.0
0.0
0.0
0.0
0.0
-18
-17
-20
-21
-20
25
20
20
18
16
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
0.4
0.9
-0.4
-0.9
-0.9
8.07
7.55
7.99
8.55
8.38
0.0
0.0
0.0
-0.5
0.0
-23
-19
-17
-27
-23
16
19
18
16
20
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
-0.1
-0.1
1.2
1.3
0.6
7.44
8.09
8.33
9.57
8.27
0.0
0.0
2.0
0.5
0.0
-18
-20
-27
-28
-25
18
20
23
24
19
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
613
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
6.25mcg
101 Day 1
10 mins
101
0.9
7.09
0.0
-24
25
1 hour
101 -0.3
7.40
0.0
-24
22
2 hours
101
1.0
7.23
0.0
-15
20
4 hours
101
0.3
8.52
0.0
-25
20
99
97
97
97
97
-1.3
-1.2
-0.3
-1.3
-0.9
8.60
8.20
9.39
9.05
8.20
0.0
0.0
0.0
0.0
0.0
-28
-28
-25
-23
-22
22
17
22
20
20
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
-2.3
-2.0
-1.3
-1.8
-0.9
9.13
8.43
9.61
9.78
9.55
-2.0
-2.0
0.0
-1.0
-2.0
-26
-27
-25
-28
-21
31
17
20
24
21
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
-0.2
-2.2
-1.6
-0.7
0.6
8.01
8.67
8.57
8.64
8.49
0.0
-2.0
-2.0
0.0
0.0
-18
-25
-19
-23
-18
19
25
25
19
28
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
614
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
12.5mcg
100 Day 1
10 mins
100 -0.4
5.23
0.0
-20
14
1 hour
99
0.5
6.87
0.0
-19
16
2 hours
99 -0.3
7.59
0.0
-27
22
4 hours
99
0.7
7.15
0.0
-22
26
97
96
95
95
93
-1.2
-1.9
-0.7
-1.4
0.1
8.07
7.90
8.17
7.44
7.71
-1.0
-2.0
0.0
0.0
0.0
-25
-24
-24
-20
-16
20
24
18
20
27
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
-1.7
-2.1
-0.5
-1.5
-0.2
9.44
9.64
9.46
8.78
9.29
-1.0
0.0
0.0
0.0
0.0
-30
-33
-30
-30
-25
20
15
25
15
22
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
-1.0
-1.3
-1.0
-0.3
-1.0
7.66
8.49
8.33
9.13
8.78
0.0
-1.5
-1.0
0.0
0.0
-21
-21
-16
-22
-26
22
20
18
32
20
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
615
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
25mcg
101 Day 1
10 mins
101
1.2
6.49
1.0
-18
28
1 hour
101
0.7
7.05
0.0
-21
26
2 hours
101
1.4
7.61
1.0
-26
30
4 hours
101
1.8
7.62
1.0
-30
28
97
95
96
96
96
-1.1
-1.1
-0.5
-1.0
-0.3
8.15
8.90
8.80
7.84
8.17
-2.0
0.0
0.0
0.0
0.0
-20
-30
-26
-30
-32
20
30
22
14
20
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
-0.8
-1.7
-0.6
-1.0
-1.3
9.19
9.30
9.43
9.69
9.62
-1.0
0.0
0.0
0.0
0.0
-29
-26
-30
-26
-26
22
22
22
27
21
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
-0.4
-1.8
-0.8
-0.0
-0.7
9.57
8.90
8.54
9.99
9.52
0.0
-1.0
0.0
0.0
0.0
-28
-25
-20
-30
-30
29
22
20
29
22
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
616
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
50mcg
102 Day 1
10 mins
102
0.1
7.00
0.0
-21
20
1 hour
102
0.3
7.43
0.0
-23
26
2 hours
102
0.8
7.99
0.0
-20
21
4 hours
102
1.3
7.53
1.0
-16
17
100
100
100
100
99
-0.3
-0.1
-0.5
1.5
0.4
8.04
8.21
8.40
8.59
8.18
0.0
0.0
0.0
1.0
0.0
-20
-24
-20
-20
-21
25
20
20
32
18
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
-0.1
-0.7
-0.5
0.1
-0.0
8.21
8.37
8.10
8.08
8.53
0.0
0.0
0.0
0.0
0.0
-18
-31
-20
-20
-22
25
21
17
22
20
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
0.7
-0.8
0.3
0.9
1.4
8.58
8.82
8.78
8.76
8.72
0.0
0.0
0.0
0.0
2.0
-30
-30
-26
-30
-29
23
19
23
19
20
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
617
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) Placebo
102 Day 1
10 mins
102 -1.2
7.53
0.0
-25
29
1 hour
102 -3.2
7.91
-2.0
-25
13
2 hours
102 -2.2
9.03
-0.5
-27
21
4 hours
102 -2.0
8.99
-2.0
-27
28
95
93
93
93
93
1.3
0.2
-0.5
-0.0
0.6
9.01
10.52
9.78
10.68
9.76
0.0
1.0
0.0
0.0
0.0
-22
-28
-24
-21
-34
24
39
40
34
29
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
90
90
90
89
2.1
0.1
-0.5
0.2
1.4
11.84
9.97
10.13
10.14
11.14
2.0
0.0
0.0
0.0
2.0
-26
-23
-26
-22
-24
39
44
38
30
30
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
88
87
87
87
87
1.2
-1.1
-1.4
-2.7
-1.8
10.91
10.40
10.32
9.61
9.64
1.0
-1.0
-2.0
-2.0
-1.0
-30
-31
-29
-30
-24
36
22
30
25
29
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
618
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 3mcg
101 Day 1
10 mins
101 -1.7
5.76
-2.0
-19
12
1 hour
101 -2.0
7.44
-2.0
-27
16
2 hours
101 -3.6
6.86
-4.0
-24
13
4 hours
101 -2.4
8.43
-2.0
-26
22
95
93
93
93
93
0.3
-0.6
-1.5
-1.0
0.0
9.00
7.87
8.19
8.94
8.65
0.0
-1.0
-2.0
0.0
0.0
-23
-19
-26
-30
-28
24
26
22
17
20
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
86
86
86
86
1.3
-0.5
-1.3
-0.6
-0.5
10.65
8.68
8.36
9.26
8.57
0.0
-1.0
-1.0
-1.5
-1.0
-29
-29
-24
-26
-21
43
22
16
22
19
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
86
85
85
84
84
0.8
-0.5
-0.9
-2.0
-1.2
9.37
9.09
8.75
9.50
10.29
0.0
0.0
-1.0
-2.5
-1.0
-24
-28
-30
-28
-24
24
26
28
26
36
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
619
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 6.25mcg
101 Day 1
10 mins
101 -0.6
6.40
-1.0
-16
26
1 hour
101 -2.3
6.28
-2.0
-18
14
2 hours
101 -3.0
8.07
-2.0
-22
34
4 hours
101 -2.4
8.23
-2.0
-23
30
99
97
97
97
97
1.6
1.6
-0.8
-0.8
-0.9
9.90
9.58
9.97
9.40
9.40
2.0
1.0
-2.0
-2.0
-1.0
-25
-20
-20
-21
-20
29
34
35
22
30
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
93
2.1
1.4
-0.8
-0.8
-0.4
12.32
9.35
8.98
9.40
10.03
0.0
0.0
-2.0
-2.0
0.0
-20
-18
-20
-23
-23
45
27
21
23
32
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
1.5
-0.1
-1.6
-2.3
-3.0
11.25
10.29
10.90
10.65
9.95
0.0
0.0
-2.0
-3.0
-2.0
-26
-20
-27
-28
-31
29
31
29
34
26
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
620
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 12.5mcg
100 Day 1
10 mins
100 -2.1
7.02
-2.0
-28
16
1 hour
99 -3.8
7.39
-4.0
-34
14
2 hours
99 -4.4
7.95
-4.0
-38
12
4 hours
99 -3.6
8.26
-3.0
-26
12
97
96
95
95
93
-0.4
-1.0
-2.7
-2.5
-1.3
9.27
9.89
10.59
9.90
8.34
0.0
-2.0
-4.0
-3.0
-2.0
-24
-22
-25
-24
-22
26
31
36
25
23
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
91
91
91
91
1.2
0.8
-0.2
0.2
-1.1
9.80
9.99
11.46
9.55
8.12
0.0
0.0
0.0
0.0
-1.0
-23
-30
-31
-25
-22
24
25
45
27
17
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
-0.2
-1.3
-2.7
-3.6
-4.3
10.34
9.92
10.57
10.12
9.62
-1.0
-1.0
-4.0
-3.5
-3.5
-32
-30
-33
-34
-33
31
27
38
20
16
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
621
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 25mcg
101 Day 1
10 mins
101 -0.1
7.03
0.0
-20
20
1 hour
101 -1.9
6.84
-1.0
-20
15
2 hours
101 -3.5
7.18
-4.0
-26
15
4 hours
101 -2.5
7.88
-2.0
-26
31
97
95
96
96
96
1.8
1.0
-0.6
-1.4
-0.6
7.77
7.74
7.31
8.25
8.27
1.0
1.0
-0.5
-2.0
-2.0
-15
-17
-20
-31
-20
23
20
18
18
23
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
94
94
94
2.0
1.9
-0.0
0.6
0.3
8.98
8.54
8.59
8.59
9.42
2.0
1.0
0.0
0.0
1.0
-22
-21
-27
-18
-21
30
27
22
21
20
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
1.4
0.7
-0.8
-2.1
-2.8
8.36
8.97
9.27
9.21
8.96
2.0
1.0
-1.0
-2.0
-3.0
-20
-21
-22
-25
-25
26
28
25
25
19
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
622
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs
Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 50mcg
102 Day 1
10 mins
102 -0.5
6.10
0.0
-20
22
1 hour
102 -1.7
6.73
-1.0
-24
12
2 hours
102 -1.9
6.70
-2.0
-20
24
4 hours
102 -1.9
8.14
-0.5
-25
20
100
100
100
100
99
0.8
2.2
1.0
0.9
0.9
9.00
10.04
8.67
8.69
9.05
0.0
1.5
2.0
1.5
0.0
-22
-32
-19
-24
-23
26
32
23
24
25
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
97
97
97
97
2.0
3.6
3.1
2.2
1.0
10.12
10.44
10.14
10.06
9.62
2.0
2.0
3.0
2.0
3.0
-21
-21
-25
-23
-25
34
44
46
32
31
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
98
98
98
98
1.6
3.5
1.7
-0.2
-0.1
10.18
9.80
8.97
9.02
9.51
2.0
3.0
2.0
0.0
0.5
-20
-19
-20
-21
-20
38
37
31
26
20
YM2008/00019/00
B2C109575
CONFIDENTIAL
Pre-dose
10 mins
1 hour
2 hours
4 hours
623
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.20
Summary of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
6.6
7.0
6.4
5.1
5.3
6.2
SD
10.76
10.08
8.61
8.56
9.08
8.97
Median
6.0
4.0
6.0
4.0
4.0
5.0
Min.
-31
-14
-13
-21
-25
-14
Max.
40
37
28
34
46
39
93
4.1
11.43
3.0
-26
38
93
6.0
10.48
5.0
-20
35
97
3.9
11.60
4.0
-35
35
96
5.3
10.34
4.0
-18
42
96
3.5
9.13
4.0
-30
30
100
5.9
10.26
5.0
-13
33
Day 14
n
Mean
SD
Median
Min.
Max.
90
5.2
12.21
6.0
-44
36
86
3.9
9.11
2.5
-16
30
93
3.8
11.75
1.0
-29
45
91
4.4
11.14
3.0
-35
31
94
3.9
10.97
3.0
-26
29
98
6.4
11.19
5.0
-24
41
Day 28
n
Mean
SD
Median
Min.
Max.
87
4.8
13.60
5.0
-27
49
85
5.4
10.58
6.0
-15
35
91
3.1
11.16
0.0
-27
31
88
4.4
11.10
4.0
-28
40
93
2.9
10.74
5.0
-25
28
98
5.1
10.65
5.5
-22
33
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
624
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.21
Summary of Maximum Increase from Pre-Dose in Systolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
5.4
6.5
6.5
7.8
4.6
7.9
SD
7.70
9.75
9.08
8.69
7.41
8.44
Median
5.0
7.0
5.0
7.0
4.0
8.0
Min.
-26
-22
-12
-12
-19
-6
Max.
28
36
44
33
20
41
n
Mean
SD
Median
Min.
Max.
90
6.6
9.08
6.0
-20
26
86
5.4
7.65
4.5
-10
28
93
7.0
10.12
6.0
-22
42
91
6.0
6.98
6.0
-8
32
94
7.1
8.64
5.5
-9
36
98
7.0
8.60
5.0
-10
48
Day 28
n
Mean
SD
Median
Min.
Max.
87
6.1
7.42
6.0
-16
27
85
7.0
8.56
5.0
-14
30
91
5.3
9.52
6.0
-12
43
88
4.7
8.93
4.0
-20
45
93
4.2
7.71
2.0
-14
28
98
4.9
9.00
4.0
-17
26
CONFIDENTIAL
625
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
6.5 (0.86)
6.5 (0.87)
6.0 (0.86)
6.2 (0.87)
5.5 (0.86)
6.0 (0.86)
Column vs Placebo
Difference
95% C.I.
p-value
0.0
(-2.4, 2.4)
0.981
-0.5
(-2.9, 1.9)
0.667
-0.3
(-2.7, 2.1)
0.823
-1.0
(-3.4, 1.4)
0.430
-0.5
(-2.9, 1.9)
0.665
CONFIDENTIAL
626
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 3.9 (0.97)
5.2 (0.97)
3.4 (0.95)
6.5 (0.95)
4.0 (0.95)
5.8 (0.94)
Column vs Placebo
Difference
95% C.I.
p-value
1.3
(-1.4, 4.0)
0.346
-0.5
(-3.1, 2.2)
0.720
2.7
(0.0, 5.3)
0.052
0.1
(-2.5, 2.8)
0.930
1.9
(-0.8, 4.6)
0.162
CONFIDENTIAL
627
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) 4.7 (1.03)
3.2 (1.06)
3.3 (1.01)
5.6 (1.02)
4.5 (1.01)
6.2 (0.99)
Column vs Placebo
Difference
95% C.I.
p-value
-1.5
(-4.4, 1.5)
0.328
-1.3
(-4.2, 1.5)
0.353
0.9
(-1.9, 3.8)
0.521
-0.2
(-3.1, 2.6)
0.879
1.5
(-1.4, 4.3)
0.305
CONFIDENTIAL
628
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 4.5 (1.02)
4.3 (1.03)
2.9 (0.99)
5.6 (1.01)
3.6 (0.98)
4.8 (0.96)
Column vs Placebo
Difference
95% C.I.
p-value
-0.2
(-3.0, 2.7)
0.897
-1.5
(-4.3, 1.3)
0.285
1.1
(-1.7, 3.9)
0.433
-0.9
(-3.7, 1.9)
0.528
0.3
(-2.5, 3.1)
0.833
CONFIDENTIAL
629
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.23
Summary of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
-3.0
-3.5
-4.0
-4.2
-2.5
-4.5
SD
6.88
6.60
7.23
6.22
7.01
6.88
Median
-3.0
-2.0
-4.0
-4.0
-2.0
-4.0
Min.
-28
-22
-25
-27
-30
-23
Max.
20
12
18
10
26
10
93
-5.0
7.87
-4.0
-28
13
93
-4.1
7.42
-4.0
-21
14
97
-5.5
8.21
-4.0
-28
16
96
-5.1
7.78
-5.5
-24
24
96
-5.1
7.35
-4.0
-32
14
100
-4.7
7.92
-4.0
-24
12
Day 14
n
Mean
SD
Median
Min.
Max.
90
-4.7
9.00
-4.5
-32
20
86
-4.3
7.78
-4.0
-27
14
93
-6.6
8.55
-6.0
-28
11
91
-5.6
8.95
-4.0
-33
15
94
-5.2
9.13
-4.0
-30
21
98
-4.8
7.56
-4.5
-31
11
Day 28
n
Mean
SD
Median
Min.
Max.
87
-3.3
7.99
-3.0
-20
24
85
-3.6
8.22
-3.0
-28
14
91
-5.6
8.09
-5.0
-25
16
88
-5.3
8.04
-5.0
-26
16
93
-5.3
8.77
-6.0
-30
16
98
-4.3
8.57
-3.5
-30
11
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
630
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.24
Summary of Maximum Decrease from Pre-Dose in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
-4.5
-5.0
-4.2
-3.9
-4.0
-4.5
SD
6.71
6.32
6.00
5.79
6.04
7.41
Median
-4.0
-4.0
-4.0
-3.0
-3.0
-3.5
Min.
-26
-21
-22
-27
-20
-25
Max.
12
20
8
16
10
12
n
Mean
SD
Median
Min.
Max.
90
-4.5
7.30
-4.0
-37
26
86
-4.5
5.78
-4.0
-19
9
93
-4.1
6.75
-3.0
-34
12
91
-4.0
5.75
-3.0
-17
10
94
-4.5
6.74
-4.0
-22
18
98
-4.7
6.72
-4.0
-29
10
Day 28
n
Mean
SD
Median
Min.
Max.
87
-3.7
6.00
-4.0
-22
26
85
-3.5
5.56
-4.0
-20
10
91
-5.4
5.54
-5.0
-24
6
88
-4.4
5.30
-4.0
-20
7
93
-4.8
6.09
-4.0
-26
8
98
-5.0
7.11
-4.0
-28
6
CONFIDENTIAL
631
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE) -2.5 (0.61) -4.0 (0.61)
-4.1 (0.61)
-3.6 (0.61)
-2.3 (0.61)
-5.1 (0.61)
Column vs Placebo
Difference
95% C.I.
p-value
-1.5
(-3.2, 0.2)
0.088
-1.5
(-3.2, 0.2)
0.078
-1.1
(-2.8, 0.6)
0.211
0.2
(-1.5, 1.9)
0.827
-2.5
(-4.2, -0.8)
0.004
CONFIDENTIAL
632
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) -4.6 (0.69)
-4.6 (0.69)
-5.5 (0.67)
-4.4 (0.67)
-4.8 (0.67)
-5.6 (0.66)
Column vs Placebo
Difference
95% C.I.
p-value
0.0
(-1.9, 1.9)
0.986
-0.9
(-2.8, 0.9)
0.329
0.2
(-1.7, 2.1)
0.835
-0.2
(-2.1, 1.6)
0.807
-1.0
(-2.9, 0.9)
0.300
CONFIDENTIAL
633
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) -4.3 (0.75)
-5.0 (0.77)
-6.4 (0.73)
-5.0 (0.74)
-4.9 (0.73)
-5.7 (0.72)
Column vs Placebo
Difference
95% C.I.
p-value
-0.7
(-2.8, 1.5)
0.540
-2.1
(-4.1, 0.0)
0.049
-0.7
(-2.8, 1.4)
0.516
-0.5
(-2.6, 1.5)
0.600
-1.4
(-3.4, 0.7)
0.187
CONFIDENTIAL
634
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) -3.1 (0.77)
-4.2 (0.78)
-5.2 (0.75)
-4.8 (0.77)
-5.2 (0.74)
-4.9 (0.73)
Column vs Placebo
Difference
95% C.I.
p-value
-1.1
(-3.2, 1.1)
0.338
-2.0
(-4.2, 0.1)
0.058
-1.7
(-3.8, 0.4)
0.120
-2.0
(-4.2, 0.1)
0.057
-1.8
(-3.9, 0.3)
0.095
CONFIDENTIAL
635
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.26
Summary of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
3.2
2.0
2.0
1.1
2.9
3.0
SD
7.45
7.01
6.81
7.11
6.98
6.38
Median
4.0
2.0
1.0
2.0
2.0
2.5
Min.
-15
-19
-12
-26
-16
-15
Max.
29
22
34
16
31
24
93
4.7
10.02
4.0
-20
40
93
4.4
8.34
4.0
-19
26
97
4.7
9.58
4.0
-18
35
96
3.4
9.59
2.0
-20
36
96
3.8
7.60
4.0
-15
23
100
6.4
9.05
6.0
-13
32
Day 14
n
Mean
SD
Median
Min.
Max.
90
5.1
10.74
4.0
-20
44
86
4.0
9.01
4.0
-18
22
93
4.4
9.56
4.0
-18
32
91
5.5
10.09
4.0
-22
45
94
5.3
8.32
5.5
-18
27
98
7.1
10.40
6.0
-21
46
Day 28
n
Mean
SD
Median
Min.
Max.
87
2.8
10.09
3.0
-21
30
85
3.4
9.14
4.0
-20
36
91
3.4
10.74
3.0
-19
34
88
2.3
9.85
1.5
-22
38
93
3.7
9.07
4.0
-20
28
98
5.9
9.30
4.5
-13
37
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
636
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.27
Summary of Maximum Increase from Pre-Dose in Pulse Rate (beats/min) (0-4hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
3.3
4.3
3.2
3.8
1.9
5.7
SD
7.48
6.54
6.46
7.23
6.05
7.28
Median
2.0
4.0
2.0
2.5
2.0
4.0
Min.
-12
-12
-12
-15
-14
-12
Max.
30
33
24
24
16
30
n
Mean
SD
Median
Min.
Max.
90
3.0
8.92
2.0
-33
40
86
3.0
6.80
2.0
-11
23
93
2.3
8.65
2.0
-23
31
91
4.2
6.15
4.0
-8
33
94
3.4
6.23
3.5
-12
19
98
5.1
6.37
4.5
-8
20
Day 28
n
Mean
SD
Median
Min.
Max.
87
1.6
6.54
1.0
-20
20
85
2.6
5.45
2.0
-15
16
91
1.9
6.68
2.0
-15
18
88
2.6
5.21
2.0
-11
18
93
2.5
6.40
2.0
-14
27
98
4.2
6.24
4.0
-14
30
CONFIDENTIAL
637
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
3.2 (0.64)
1.9 (0.64)
1.6 (0.64)
1.3 (0.64)
3.1 (0.64)
3.1 (0.64)
Column vs Placebo
Difference
95% C.I.
p-value
-1.4
(-3.1, 0.4)
0.134
-1.7
(-3.4, 0.1)
0.068
-1.9
(-3.7, -0.1)
0.035
-0.2
(-1.9, 1.6)
0.858
-0.1
(-1.9, 1.6)
0.871
CONFIDENTIAL
638
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 4.7 (0.80)
4.1 (0.80)
4.1 (0.78)
4.0 (0.78)
4.1 (0.78)
6.3 (0.77)
Column vs Placebo
Difference
95% C.I.
p-value
-0.6
(-2.8, 1.6)
0.590
-0.6
(-2.8, 1.5)
0.561
-0.7
(-2.9, 1.5)
0.533
-0.6
(-2.8, 1.6)
0.592
1.6
(-0.6, 3.8)
0.157
CONFIDENTIAL
639
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) 5.2 (0.87)
3.4 (0.89)
3.7 (0.85)
6.1 (0.86)
5.8 (0.85)
7.2 (0.83)
Column vs Placebo
Difference
95% C.I.
p-value
-1.8
(-4.2, 0.7)
0.156
-1.5
(-3.9, 0.9)
0.212
0.9
(-1.5, 3.3)
0.479
0.6
(-1.8, 2.9)
0.642
2.0
(-0.4, 4.3)
0.103
CONFIDENTIAL
640
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 3.0 (0.88)
3.1 (0.89)
2.7 (0.86)
2.8 (0.88)
4.0 (0.85)
5.7 (0.83)
Column vs Placebo
Difference
95% C.I.
p-value
0.1
(-2.3, 2.6)
0.910
-0.3
(-2.7, 2.1)
0.801
-0.2
(-2.6, 2.3)
0.904
1.0
(-1.4, 3.4)
0.406
2.7
(0.3, 5.1)
0.026
CONFIDENTIAL
641
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.29
Summary of Weighted Mean Change from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
0.99
1.49
0.75
-0.35
0.16
0.69
SD
10.132
8.686
7.493
7.646
7.752
7.794
Median
1.79
0.46
0.41
0.00
0.34
0.00
Min.
-32.5
-17.3
-16.5
-23.8
-31.3
-19.2
Max.
29.2
24.8
19.0
21.7
27.0
23.8
92
-0.76
11.526
-0.32
-31.1
31.5
92
0.23
10.267
-0.39
-20.1
30.4
97
-1.92
10.634
-1.92
-37.4
26.5
93
-0.06
9.288
0.00
-22.1
24.9
96
-1.04
8.680
-0.44
-29.8
22.2
99
0.16
9.329
-0.37
-23.7
22.9
Day 14
n
Mean
SD
Median
Min.
Max.
89
-0.65
11.574
0.00
-44.6
26.8
86
-1.20
9.271
-2.64
-25.4
25.4
93
-2.16
10.118
-3.02
-33.0
21.4
91
-0.49
11.019
-0.15
-39.7
23.7
94
-1.62
9.515
-0.40
-31.9
17.8
96
0.62
10.157
1.42
-26.8
27.7
Day 28
n
Mean
SD
Median
Min.
Max.
87
-0.42
13.123
0.50
-30.1
40.4
84
-0.66
9.794
0.00
-22.6
25.4
91
-2.53
10.985
-3.26
-43.5
23.1
88
-0.70
10.034
-0.78
-30.7
32.1
93
-1.90
9.908
-0.08
-27.5
20.1
97
-0.27
10.499
0.63
-28.9
24.7
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
642
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.30
Summary of Weighted Mean Change from Pre-Dose in Systolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
0.45
0.77
0.65
2.32
0.14
2.16
SD
7.995
9.094
7.441
7.254
6.761
7.009
Median
1.09
1.18
-0.30
1.30
0.00
2.09
Min.
-28.8
-27.3
-15.1
-13.8
-21.4
-15.0
Max.
22.9
28.3
21.7
26.3
14.6
27.7
n
Mean
SD
Median
Min.
Max.
89
0.81
8.207
1.68
-23.9
17.1
86
0.29
7.062
0.35
-14.4
19.6
93
1.06
8.968
1.13
-28.9
27.8
91
1.15
6.304
1.29
-13.5
17.8
94
1.57
7.708
1.11
-15.0
28.1
96
1.39
7.557
0.00
-12.2
33.3
Day 28
n
Mean
SD
Median
Min.
Max.
87
0.90
7.139
0.95
-21.5
23.5
84
1.11
8.229
0.12
-21.9
22.6
91
-0.30
8.223
0.26
-22.3
17.6
88
-0.35
7.723
-0.06
-23.5
25.8
93
-0.61
7.789
-1.08
-25.6
23.9
97
-0.62
8.707
-0.72
-23.9
18.7
CONFIDENTIAL
643
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE)
1.0 (0.74)
1.0 (0.75)
0.4 (0.74)
0.7 (0.75)
0.4 (0.75)
0.3 (0.74)
Column vs Placebo
Difference
95% C.I.
p-value
0.0
(-2.1, 2.1)
0.997
-0.6
(-2.6, 1.5)
0.582
-0.3
(-2.4, 1.8)
0.785
-0.6
(-2.7, 1.5)
0.573
-0.7
(-2.7, 1.4)
0.526
CONFIDENTIAL
644
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) -0.8 (0.92)
-0.5 (0.92)
-2.4 (0.89)
1.0 (0.91)
-0.6 (0.89)
-0.1 (0.88)
Column vs Placebo
Difference
95% C.I.
p-value
0.4
(-2.2, 2.9)
0.788
-1.6
(-4.1, 0.9)
0.218
1.9
(-0.7, 4.4)
0.148
0.3
(-2.2, 2.8)
0.837
0.7
(-1.8, 3.2)
0.577
CONFIDENTIAL
645
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) -1.1 (0.95)
-1.8 (0.97)
-2.5 (0.93)
0.7 (0.94)
-1.1 (0.92)
0.3 (0.91)
Column vs Placebo
Difference
95% C.I.
p-value
-0.7
(-3.4, 2.0)
0.601
-1.5
(-4.1, 1.1)
0.269
1.7
(-0.9, 4.3)
0.200
-0.1
(-2.7, 2.5)
0.947
1.3
(-1.3, 3.9)
0.319
CONFIDENTIAL
646
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -0.6 (0.97)
-1.5 (0.99)
-2.6 (0.95)
0.4 (0.96)
-1.5 (0.94)
-0.7 (0.92)
Column vs Placebo
Difference
95% C.I.
p-value
-0.9
(-3.6, 1.8)
0.524
-2.0
(-4.7, 0.6)
0.134
0.9
(-1.8, 3.6)
0.491
-0.9
(-3.6, 1.7)
0.502
-0.1
(-2.8, 2.5)
0.913
CONFIDENTIAL
647
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.32
Summary of Weighted Mean Change from Baseline in Diastolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
1.49
1.37
0.49
0.13
1.39
0.74
SD
6.324
6.480
6.476
5.742
6.444
6.017
Median
1.40
1.79
0.85
0.29
0.81
0.92
Min.
-23.2
-13.0
-17.4
-17.3
-23.2
-13.0
Max.
22.0
19.7
19.9
16.4
27.9
14.4
92
-0.67
7.464
-0.66
-26.5
18.4
92
0.46
6.722
-0.07
-14.2
15.3
97
-0.98
7.885
-0.39
-21.8
18.7
93
-0.87
6.468
-1.13
-15.5
16.5
96
-0.72
7.325
-0.04
-29.3
18.0
99
0.51
7.249
0.50
-19.1
18.1
Day 14
n
Mean
SD
Median
Min.
Max.
89
-0.09
8.692
-0.08
-24.0
23.4
86
-0.56
7.530
-0.19
-21.8
15.5
93
-1.50
8.662
-1.49
-22.8
18.3
91
-1.01
8.247
0.00
-27.4
17.5
94
-1.03
8.864
-0.18
-27.0
23.6
96
-0.22
7.107
-1.09
-15.8
17.8
Day 28
n
Mean
SD
Median
Min.
Max.
87
0.61
8.411
0.01
-18.3
27.0
84
0.87
7.861
0.78
-18.0
17.6
91
-0.73
7.453
-0.65
-16.2
19.6
88
-0.74
7.866
-0.04
-21.3
22.5
93
-0.59
8.529
-0.70
-26.0
21.2
97
0.66
7.675
0.43
-25.8
15.2
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
648
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.33
Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood Pressure (mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
-0.28
-0.25
0.32
0.54
0.41
0.77
SD
5.652
5.663
5.665
5.076
5.598
5.954
Median
0.07
-0.17
0.00
0.14
0.00
0.53
Min.
-18.5
-17.1
-14.2
-11.8
-13.8
-14.9
Max.
15.4
19.7
13.9
20.5
17.5
18.3
n
Mean
SD
Median
Min.
Max.
89
0.18
7.001
0.64
-35.3
27.9
86
-0.77
5.709
-0.58
-12.6
15.4
93
0.98
6.463
1.17
-23.3
17.6
91
0.66
5.382
0.66
-11.8
19.4
94
-0.29
6.384
0.10
-21.5
22.5
96
-0.14
5.523
-0.01
-25.6
16.4
Day 28
n
Mean
SD
Median
Min.
Max.
87
0.19
5.552
0.16
-11.1
28.1
84
1.02
5.089
1.13
-11.1
17.3
91
-0.50
4.900
0.00
-13.2
9.8
88
0.16
4.900
0.00
-14.8
12.4
93
-0.08
5.097
0.00
-12.1
13.6
97
-0.17
6.602
0.00
-17.2
22.8
CONFIDENTIAL
649
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE)
1.9 (0.54)
0.8 (0.55)
0.4 (0.54)
0.7 (0.55)
1.5 (0.55)
0.2 (0.54)
Column vs Placebo
Difference
95% C.I.
p-value
-1.1
(-2.7, 0.4)
0.148
-1.5
(-3.0, 0.0)
0.052
-1.2
(-2.7, 0.3)
0.111
-0.4
(-1.9, 1.1)
0.629
-1.7
(-3.2, -0.2)
0.030
CONFIDENTIAL
650
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) -0.3 (0.64)
0.0 (0.64)
-1.0 (0.62)
-0.2 (0.63)
-0.5 (0.62)
-0.1 (0.61)
Column vs Placebo
Difference
95% C.I.
p-value
0.3
(-1.4, 2.1)
0.710
-0.7
(-2.4, 1.0)
0.437
0.1
(-1.6, 1.9)
0.894
-0.1
(-1.9, 1.6)
0.879
0.2
(-1.5, 1.9)
0.819
CONFIDENTIAL
651
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) 0.1 (0.73)
-1.1 (0.74)
-1.3 (0.71)
-0.4 (0.72)
-0.7 (0.71)
-1.0 (0.70)
Column vs Placebo
Difference
95% C.I.
p-value
-1.3
(-3.3, 0.8)
0.230
-1.4
(-3.4, 0.6)
0.177
-0.5
(-2.5, 1.5)
0.632
-0.8
(-2.8, 1.2)
0.406
-1.1
(-3.1, 0.9)
0.277
CONFIDENTIAL
652
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) 0.7 (0.73)
0.2 (0.74)
-0.3 (0.71)
-0.3 (0.72)
-0.4 (0.70)
0.1 (0.69)
Column vs Placebo
Difference
95% C.I.
p-value
-0.5
(-2.6, 1.5)
0.613
-1.0
(-3.0, 1.0)
0.312
-1.0
(-3.0, 1.0)
0.332
-1.1
(-3.1, 0.9)
0.280
-0.6
(-2.6, 1.4)
0.550
CONFIDENTIAL
653
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.35
Summary of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
-2.20
-2.59
-2.36
-3.74
-2.37
-1.64
SD
7.064
6.355
6.517
6.699
6.051
5.850
Median
-1.38
-2.12
-1.71
-4.00
-2.01
-1.02
Min.
-21.9
-24.1
-16.8
-32.0
-23.2
-18.5
Max.
16.3
12.2
24.9
10.5
16.7
15.2
92
-0.03
9.330
-0.10
-24.8
34.5
92
-0.89
7.372
-0.13
-24.8
14.1
97
-0.52
8.686
-1.30
-19.1
26.3
93
-2.01
8.670
-2.34
-21.3
25.5
96
-0.67
7.098
-0.52
-23.3
17.3
99
1.12
7.797
1.26
-16.4
19.0
Day 14
n
Mean
SD
Median
Min.
Max.
89
0.32
9.615
-0.14
-22.5
33.7
86
-0.68
7.929
-1.10
-21.8
14.2
93
-0.37
8.659
-0.66
-20.3
19.0
91
-0.14
8.493
-0.31
-25.7
26.9
94
0.57
7.863
0.51
-21.2
17.4
96
2.34
9.247
2.52
-22.4
32.0
Day 28
n
Mean
SD
Median
Min.
Max.
87
-1.93
9.028
-1.01
-27.6
25.0
84
-1.32
8.678
-1.00
-23.3
26.3
91
-1.98
9.643
-1.82
-27.2
29.6
88
-3.22
9.066
-3.51
-30.2
18.7
93
-1.56
8.070
-1.16
-20.6
14.3
97
0.76
8.557
1.04
-17.8
25.8
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
654
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.36
Summary of Weighted Mean Change from Pre-Dose in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
-1.32
-0.77
-2.05
-1.43
-2.54
0.34
SD
6.813
6.571
6.234
6.141
5.809
6.436
Median
-1.02
-0.48
-1.19
-2.78
-1.08
0.75
Min.
-16.8
-22.4
-21.2
-13.9
-19.0
-17.8
Max.
21.5
30.3
11.9
13.1
10.3
17.5
n
Mean
SD
Median
Min.
Max.
89
-1.65
8.133
-0.73
-35.1
29.8
86
-1.67
6.656
-1.71
-17.5
16.0
93
-2.51
8.524
-1.38
-35.5
18.0
91
-1.38
5.963
-1.04
-17.4
14.9
94
-1.41
5.708
-1.76
-17.3
9.5
96
0.29
5.850
0.63
-13.5
16.1
Day 28
n
Mean
SD
Median
Min.
Max.
87
-3.12
6.373
-2.62
-31.2
11.1
84
-2.18
5.152
-1.49
-21.1
12.5
91
-3.51
6.674
-3.07
-24.7
10.4
88
-2.90
5.372
-2.41
-19.8
9.0
93
-2.78
6.104
-2.55
-22.9
14.5
97
-0.86
6.683
-0.17
-20.4
24.3
CONFIDENTIAL
655
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE) -2.0 (0.57) -2.8 (0.58)
-2.8 (0.57)
-3.4 (0.58)
-2.3 (0.58)
-1.6 (0.57)
Column vs Placebo
Difference
95% C.I.
p-value
-0.8
(-2.4, 0.8)
0.315
-0.8
(-2.4, 0.8)
0.343
-1.4
(-3.0, 0.2)
0.093
-0.3
(-1.9, 1.3)
0.731
0.4
(-1.2, 2.0)
0.615
CONFIDENTIAL
656
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) 0.1 (0.71)
-1.1 (0.71)
-1.0 (0.69)
-1.5 (0.71)
-0.4 (0.70)
1.0 (0.69)
Column vs Placebo
Difference
95% C.I.
p-value
-1.2
(-3.2, 0.8)
0.234
-1.1
(-3.1, 0.8)
0.261
-1.6
(-3.6, 0.4)
0.120
-0.5
(-2.5, 1.4)
0.600
0.9
(-1.1, 2.8)
0.380
CONFIDENTIAL
657
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) 0.6 (0.76)
-1.2 (0.78)
-1.0 (0.74)
0.4 (0.75)
0.9 (0.74)
2.4 (0.73)
Column vs Placebo
Difference
95% C.I.
p-value
-1.8
(-3.9, 0.4)
0.104
-1.5
(-3.6, 0.5)
0.147
-0.1
(-2.2, 2.0)
0.897
0.4
(-1.7, 2.5)
0.717
1.8
(-0.3, 3.9)
0.090
CONFIDENTIAL
658
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -1.7 (0.79)
-1.6 (0.80)
-2.6 (0.77)
-2.6 (0.78)
-1.2 (0.76)
0.5 (0.74)
Column vs Placebo
Difference
95% C.I.
p-value
0.1
(-2.1, 2.3)
0.929
-0.9
(-3.1, 1.2)
0.404
-1.0
(-3.1, 1.2)
0.389
0.4
(-1.7, 2.6)
0.696
2.2
(0.0, 4.3)
0.047
CONFIDENTIAL
659
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
Placebo
102 Day 1
Pre-dose
102
69.8 10.87
70.0
42
105
10 mins
102
65.6 10.84
64.0
30
92
1 hour
101
64.7 10.75
65.0
32
94
2 hours
101
65.0 11.45
63.0
34
108
4 hours
101
67.0 10.95
69.0
35
98
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
70.3
68.0
67.4
68.5
69.5
10.32
10.50
10.04
10.40
9.71
70.0
67.0
67.0
68.0
68.0
49
47
47
48
50
93
93
91
92
101
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
69.7
68.1
65.7
68.7
69.9
11.13
10.26
10.53
11.14
10.17
68.0
67.0
65.0
69.0
69.5
48
48
46
47
48
94
90
96
92
94
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
70.2
69.3
66.8
64.7
66.8
10.95
10.46
10.23
9.54
10.29
68.0
68.0
65.0
63.0
67.5
52
51
48
45
48
100
97
95
95
93
CONFIDENTIAL
660
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
3mcg
101 Day 1
Pre-dose
101
70.4 11.62
69.0
43
101
10 mins
97
67.1 11.05
66.0
43
98
1 hour
101
66.4 11.33
65.0
40
92
2 hours
101
64.3 10.15
63.0
40
90
4 hours
101
65.3 11.07
64.0
41
101
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
69.9
68.5
67.4
67.3
68.5
10.41
10.21
10.69
9.89
9.04
70.0
68.0
67.0
67.0
67.0
46
48
45
44
46
96
101
94
94
96
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
71.6
69.4
66.9
68.3
68.2
12.04
10.13
9.96
9.43
9.42
72.0
70.0
67.0
68.0
67.0
43
46
44
42
49
112
90
92
91
91
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
68.8
68.0
65.8
64.2
65.4
10.25
10.17
9.65
9.01
10.13
69.0
68.0
66.0
65.5
65.0
44
45
44
41
44
89
91
88
85
93
CONFIDENTIAL
661
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
6.25mcg
101 Day 1
Pre-dose
101
68.8
9.91
68.0
47
94
10 mins
100
66.0
9.17
66.0
46
92
1 hour
100
65.1 10.03
65.5
47
90
2 hours
101
63.0
9.66
62.0
46
91
4 hours
101
64.7 10.79
63.0
44
92
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
70.3
70.1
66.9
68.1
67.5
10.87
10.53
10.50
10.14
9.58
69.0
69.0
67.0
68.0
67.0
46
50
44
48
44
95
92
91
96
93
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
70.6
70.7
67.5
67.8
68.5
10.68
10.61
9.87
10.50
10.82
70.0
70.0
66.0
67.0
67.0
47
49
49
48
48
99
94
91
94
98
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
68.7
68.1
65.6
64.2
63.9
11.55
10.29
9.83
10.14
10.69
67.0
67.0
64.0
63.0
63.0
51
47
50
46
41
100
110
94
95
94
CONFIDENTIAL
662
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
12.5mcg
100 Day 1
Pre-dose
100
70.0
9.68
70.0
44
95
10 mins
99
67.2
9.65
66.0
48
90
1 hour
98
65.1
8.38
65.5
44
82
2 hours
98
64.2
8.59
64.5
44
87
4 hours
99
66.6
9.57
66.0
44
94
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
69.8
70.4
67.4
67.7
68.1
9.05
9.33
9.43
9.73
9.41
68.0
70.0
67.0
67.0
68.0
49
50
48
46
47
95
96
90
93
103
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
70.0
70.9
68.5
69.4
68.0
10.72
10.73
10.15
9.79
9.03
68.0
71.0
67.0
67.0
67.0
49
45
46
48
44
100
102
94
99
87
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
69.2
69.6
65.7
64.6
65.3
10.03
9.24
8.31
9.37
8.08
68.0
69.0
66.0
64.0
65.0
51
51
49
44
48
102
94
84
93
88
CONFIDENTIAL
663
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
25mcg
101 Day 1
Pre-dose
101
68.9 10.71
68.0
40
96
10 mins
98
68.8 11.13
68.5
42
93
1 hour
100
66.1 11.01
67.0
40
91
2 hours
100
64.5 10.15
63.5
41
89
4 hours
101
65.3 10.76
63.0
43
100
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
70.2
71.7
67.7
68.1
69.7
11.08
10.21
9.18
10.57
10.12
69.0
72.0
68.0
69.0
70.0
44
48
49
47
48
102
104
85
89
94
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
71.8
73.0
70.2
70.8
69.8
11.19
10.52
10.34
10.14
11.19
72.0
72.0
68.0
70.0
69.0
43
50
52
47
44
103
102
102
103
94
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
69.8
71.5
67.3
65.9
66.1
11.42
11.27
10.68
11.18
11.12
68.0
72.0
66.0
64.0
66.0
47
46
43
42
42
98
105
94
93
94
CONFIDENTIAL
664
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
50mcg
102 Day 1
Pre-dose
102
68.8 10.49
68.0
50
108
10 mins
102
70.0 10.95
68.5
48
101
1 hour
100
67.8 11.09
67.0
47
112
2 hours
101
67.0 11.19
65.0
47
101
4 hours
99
66.2 11.78
66.0
44
102
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
69.7
74.9
70.1
68.7
69.8
9.81
10.73
10.17
9.49
10.24
69.0
73.5
70.0
69.0
70.0
46
53
50
48
47
99
104
95
93
96
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
70.5
75.8
71.4
71.0
69.3
8.98
10.21
11.08
10.77
9.90
70.0
75.0
70.0
71.0
69.0
48
53
49
47
47
94
103
108
95
91
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
70.2
74.8
68.9
67.2
67.3
10.89
10.89
10.30
10.21
10.49
68.0
74.0
68.0
67.0
66.0
49
54
52
49
45
99
102
97
98
98
CONFIDENTIAL
665
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
Placebo
102 Day 1
Pre-dose
102 376.7 26.48 377.5
304
470
Interval (msec)
10 mins
102 383.8 28.77 387.5
314
466
1 hour
101 384.7 28.76 388.0
314
477
2 hours
101 387.5 27.35 389.0
305
459
4 hours
101 385.3 30.18 391.0
290
477
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
376.4
379.6
382.0
383.0
379.3
24.72
25.49
26.60
25.04
25.02
380.0
380.0
380.0
384.0
378.0
320
315
322
326
324
449
442
469
463
446
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
376.5
379.8
382.5
379.1
379.1
25.35
25.65
25.99
26.08
25.46
378.0
379.0
383.0
381.0
375.5
320
330
315
309
319
442
434
443
438
435
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
377.2
377.8
382.7
388.3
387.1
25.94
26.24
26.35
23.94
25.18
376.0
379.0
383.0
388.0
388.0
321
313
330
339
321
457
446
462
435
437
CONFIDENTIAL
666
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
3mcg
101 Day 1
Pre-dose
101 374.3 27.78 373.0
302
439
Interval (msec)
10 mins
97 379.9 27.08 381.0
316
462
1 hour
101 381.1 29.19 378.0
313
468
2 hours
101 386.5 27.77 386.0
317
466
4 hours
101 385.6 29.20 383.0
313
475
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
377.1
379.3
382.2
384.2
379.3
29.18
27.64
28.60
27.87
27.90
375.5
377.0
380.0
383.0
377.0
310
314
305
322
304
467
469
469
472
447
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
374.2
376.1
382.5
379.0
379.3
30.39
28.96
27.73
29.24
25.91
372.5
372.0
378.5
374.0
374.5
307
303
322
293
321
460
456
474
469
449
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
378.5
377.7
379.8
386.3
384.9
29.55
29.73
26.93
26.92
27.41
376.0
374.0
377.0
383.0
385.0
319
317
328
330
322
492
488
460
469
465
CONFIDENTIAL
667
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
6.25mcg
101 Day 1
Pre-dose
101 379.8 26.10 376.0
329
448
Interval (msec)
10 mins
100 387.0 26.28 385.0
322
449
1 hour
100 387.4 26.14 384.0
321
452
2 hours
101 391.0 27.44 386.0
330
475
4 hours
101 391.1 27.26 392.0
329
457
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
374.6
373.3
379.6
379.4
379.8
25.77
25.09
24.66
26.47
25.83
375.0
372.0
380.5
379.0
378.0
319
321
327
316
326
441
451
436
442
448
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
373.6
374.4
378.5
377.9
375.5
27.18
27.39
25.82
28.07
29.90
372.0
372.0
377.0
372.0
371.5
320
314
323
315
317
442
441
459
458
444
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
377.5
378.4
383.2
385.4
389.3
27.32
26.51
27.39
26.47
29.03
376.0
376.0
379.0
384.0
389.0
302
306
315
324
333
442
446
449
447
451
CONFIDENTIAL
668
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
12.5mcg
100 Day 1
Pre-dose
100 375.0 29.91 370.0
308
469
Interval (msec)
10 mins
99 381.7 28.59 377.0
329
460
1 hour
98 383.5 27.90 376.5
332
475
2 hours
98 387.8 27.12 384.0
343
464
4 hours
99 385.6 28.88 384.0
326
471
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
376.2
375.9
382.2
383.0
381.0
26.41
27.49
27.10
28.52
28.77
378.0
375.5
385.0
389.0
382.0
325
324
309
319
313
440
442
441
464
461
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
375.6
375.4
378.1
378.4
380.6
26.76
28.25
27.95
29.60
28.75
373.5
374.0
376.0
376.0
379.0
312
316
317
310
317
459
455
470
476
498
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
378.3
376.6
384.6
388.0
387.1
24.76
25.27
26.22
27.74
28.03
374.0
374.0
380.5
385.5
389.5
322
322
329
325
308
444
445
467
485
455
CONFIDENTIAL
669
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
25mcg
101 Day 1
Pre-dose
101 378.3 26.05 378.0
321
458
Interval (msec)
10 mins
98 379.3 27.13 379.0
311
441
1 hour
100 382.1 30.37 377.0
329
479
2 hours
100 386.8 27.57 385.0
328
451
4 hours
101 385.7 29.49 386.0
321
452
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
374.7
373.4
380.4
380.2
377.4
25.40
25.53
25.71
26.92
27.02
377.0
373.0
379.0
377.5
380.0
327
318
332
322
319
454
440
458
439
440
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
373.5
371.4
377.3
375.7
376.7
24.63
25.41
24.90
24.01
26.03
376.0
372.5
379.0
376.0
374.0
310
305
314
317
317
442
432
426
432
443
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
376.7
375.7
380.9
384.7
386.9
28.31
29.53
29.78
30.36
27.94
375.5
376.0
381.0
382.0
389.0
297
292
292
303
320
483
472
469
468
462
CONFIDENTIAL
670
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
50mcg
102 Day 1
Pre-dose
102 380.2 26.49 377.0
321
450
Interval (msec)
10 mins
102 380.7 27.60 378.0
319
449
1 hour
100 383.1 28.94 382.5
323
461
2 hours
101 387.1 30.53 388.0
299
456
4 hours
99 387.7 30.42 385.0
308
459
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
378.1
372.5
379.3
379.7
380.6
24.81
25.63
25.74
26.19
27.74
376.0
370.5
378.0
379.0
376.0
322
311
314
282
322
445
440
446
460
469
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
372.0
369.6
373.8
374.3
379.8
25.21
25.34
25.66
26.10
25.70
370.0
369.5
372.0
372.0
377.0
309
321
317
322
321
449
450
450
450
455
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
377.8
372.3
382.0
384.6
384.8
27.07
28.62
26.25
29.03
27.98
377.0
374.0
382.0
383.0
386.0
324
304
329
303
321
459
445
460
466
459
CONFIDENTIAL
671
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
Placebo
102 Day 1
Pre-dose
102 395.9 19.00 398.5
336
439
(Fridericia) (msec)
10 mins
102 395.0 22.36 396.0
330
445
1 hour
101 394.0 22.08 395.0
338
448
2 hours
101 397.3 21.54 398.0
340
450
4 hours
101 399.1 22.42 400.0
335
437
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
396.7
395.8
397.0
400.5
398.8
19.45
19.37
18.83
19.67
19.32
397.0
398.5
396.0
400.0
396.0
342
345
346
352
360
441
443
447
442
442
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
395.6
396.3
394.3
396.3
399.0
18.83
19.10
20.98
20.53
20.00
397.0
400.0
396.5
397.5
399.0
332
327
318
333
341
433
438
446
445
443
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
397.4
396.2
396.6
398.4
401.3
19.31
18.83
20.62
19.49
19.72
397.0
396.0
397.0
399.0
402.5
351
356
352
342
351
457
446
461
459
468
CONFIDENTIAL
672
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
3mcg
101 Day 1
Pre-dose
101 394.2 22.53 393.0
351
456
(Fridericia) (msec)
10 mins
97 394.1 21.43 392.0
347
455
1 hour
101 393.8 22.30 394.0
346
454
2 hours
101 395.2 19.02 394.0
361
454
4 hours
101 396.2 22.01 396.0
344
461
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
396.6
396.3
396.9
399.2
396.7
21.33
20.46
20.13
20.46
21.76
397.0
395.0
400.0
399.0
399.0
341
331
350
356
327
454
452
450
451
459
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
396.3
394.6
396.6
396.0
396.0
23.08
21.90
21.88
25.17
20.08
395.5
394.0
395.5
398.5
395.0
342
336
352
325
340
470
454
450
470
446
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
396.0
393.7
391.6
395.3
396.0
22.44
22.50
20.85
22.61
21.36
396.0
395.0
393.5
397.5
399.0
333
347
344
337
347
481
470
451
471
455
CONFIDENTIAL
673
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
6.25mcg
101 Day 1
Pre-dose
101 397.8 23.02 397.0
342
459
(Fridericia) (msec)
10 mins
100 399.7 21.65 400.5
348
453
1 hour
100 398.1 21.07 396.0
346
451
2 hours
101 397.5 19.86 398.0
357
460
4 hours
101 400.6 20.31 400.0
358
455
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
394.6
393.2
393.7
396.0
395.1
20.18
20.36
19.96
21.20
19.52
394.0
393.0
393.5
397.0
396.0
357
356
350
340
346
445
458
455
454
447
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
394.3
395.4
393.7
393.3
392.3
21.03
22.41
20.51
21.20
23.84
395.0
396.0
394.0
394.0
394.0
320
343
353
339
327
445
446
442
443
454
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
394.7
395.0
395.0
394.2
397.2
21.31
21.29
21.37
21.32
21.80
394.0
395.0
399.0
397.0
401.0
344
331
347
343
338
449
441
445
443
437
CONFIDENTIAL
674
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
12.5mcg
100 Day 1
Pre-dose
100 394.7 23.92 396.0
343
454
(Fridericia) (msec)
10 mins
99 396.6 24.72 397.0
327
457
1 hour
98 394.5 22.95 395.5
337
453
2 hours
98 396.9 23.44 395.0
339
454
4 hours
99 399.5 23.19 397.0
343
468
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
396.1
396.8
397.5
398.8
397.5
23.86
24.18
22.83
22.30
22.31
391.0
393.0
396.0
396.0
396.5
346
348
352
355
343
469
470
461
461
464
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
395.3
396.9
395.3
397.3
397.1
20.40
22.36
22.65
23.45
21.63
392.0
397.0
396.0
393.0
396.0
351
347
344
336
356
470
471
467
455
456
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
396.9
396.1
396.9
398.0
398.7
20.12
21.00
22.28
22.68
24.05
397.0
396.0
391.0
394.0
399.5
354
342
355
347
320
440
444
455
455
458
CONFIDENTIAL
675
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
25mcg
101 Day 1
Pre-dose
101 396.0 19.80 393.0
350
444
(Fridericia) (msec)
10 mins
98 396.7 23.15 397.5
341
447
1 hour
100 394.2 22.33 394.0
330
448
2 hours
100 396.2 20.25 396.0
352
442
4 hours
101 396.4 19.49 397.0
346
445
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
394.8
396.3
396.3
396.6
396.8
22.15
22.34
20.52
21.91
22.70
396.0
399.0
394.0
397.0
399.0
338
338
358
349
334
453
458
453
458
455
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
396.4
396.5
397.6
397.1
395.9
20.57
20.96
20.10
19.12
19.26
397.0
398.5
397.0
397.0
395.0
340
342
344
363
349
447
447
444
466
452
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
395.7
398.1
395.5
396.4
399.4
21.36
22.82
21.98
22.01
23.05
397.0
398.0
399.0
399.0
401.0
332
334
337
336
337
452
461
457
451
454
CONFIDENTIAL
676
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
50mcg
102 Day 1
Pre-dose
102 398.0 20.04 396.5
352
452
(Fridericia) (msec)
10 mins
102 400.7 22.36 398.0
346
468
1 hour
100 398.7 22.22 399.0
350
479
2 hours
101 400.9 20.89 402.0
339
472
4 hours
99 400.0 21.62 399.0
346
483
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
397.6
401.0
399.4
397.5
400.4
19.33
18.10
21.22
21.59
20.81
398.0
402.5
401.0
398.0
399.0
347
366
340
318
351
462
458
462
469
481
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
392.9
399.7
395.8
395.7
398.5
18.92
19.22
18.42
19.40
19.29
395.0
399.0
396.0
392.0
398.0
313
363
338
332
352
455
456
450
463
449
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
397.8
400.5
400.0
399.2
399.5
19.84
21.17
19.06
21.89
20.30
398.0
401.0
398.5
399.0
398.0
347
331
354
341
354
451
450
461
461
451
CONFIDENTIAL
677
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
Placebo
102 Day 1
Pre-dose
102 405.9 22.51 403.5
323
457
(Bazetts) (msec)
10 mins
102 400.9 26.58 402.5
312
453
1 hour
101 398.9 26.08 399.0
322
458
2 hours
101 402.4 26.77 401.0
321
467
4 hours
101 406.4 25.50 406.0
326
450
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
407.3
404.1
404.6
409.5
408.7
23.01
22.98
21.17
23.82
21.89
408.0
405.5
407.0
408.0
409.0
338
332
333
343
359
455
454
447
456
459
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
405.4
404.6
400.2
405.2
409.2
22.92
22.14
25.29
25.10
23.13
408.0
407.0
400.0
405.5
408.5
324
324
319
324
330
448
453
461
467
454
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
407.8
405.6
403.9
403.5
408.5
22.64
21.28
23.88
23.52
23.56
407.0
406.0
401.0
403.0
410.5
354
360
353
338
341
468
466
461
478
483
CONFIDENTIAL
678
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 20 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
3mcg
101 Day 1
Pre-dose
101 404.6 26.64 404.0
341
474
(Bazetts) (msec)
10 mins
97 401.4 25.31 401.0
334
471
1 hour
101 400.3 25.89 403.0
331
459
2 hours
101 399.6 21.42 399.0
357
451
4 hours
101 401.6 25.40 399.0
330
497
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
406.6
405.1
404.4
406.9
405.6
23.06
22.64
22.63
22.67
23.22
407.0
404.0
405.0
408.0
408.0
334
326
355
355
339
465
459
448
461
466
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
407.9
404.2
403.8
404.8
404.5
25.98
24.12
24.88
27.93
22.32
407.0
406.0
404.5
408.0
405.0
337
352
342
337
331
474
453
469
469
454
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
404.9
401.8
397.7
399.8
401.5
24.84
24.78
24.14
25.99
24.95
408.0
402.0
398.5
400.5
403.0
316
340
336
330
330
475
460
455
475
460
CONFIDENTIAL
679
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 21 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
6.25mcg
101 Day 1
Pre-dose
101 407.0 26.90 407.0
348
473
(Bazetts) (msec)
10 mins
100 406.1 24.64 407.0
342
463
1 hour
100 403.5 25.02 403.0
351
459
2 hours
101 400.8 22.63 400.0
353
466
4 hours
101 405.5 24.50 404.0
353
463
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
405.1
403.5
400.9
404.3
403.1
24.21
24.39
24.82
24.49
22.28
404.0
404.0
399.5
407.0
403.0
351
356
347
339
347
462
470
471
464
452
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
405.1
406.3
401.4
401.2
400.9
24.11
25.96
23.86
23.97
26.49
405.0
409.0
402.0
401.0
399.0
315
342
348
331
329
458
468
461
451
462
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
403.7
403.4
400.8
398.7
401.3
24.91
24.06
24.06
24.96
25.16
402.0
407.5
403.0
399.0
406.5
347
329
347
340
331
454
454
453
448
448
CONFIDENTIAL
680
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 22 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
12.5mcg
100 Day 1
Pre-dose
100 404.9 25.63 407.0
343
475
(Bazetts) (msec)
10 mins
99 404.2 27.76 405.0
326
470
1 hour
98 400.1 25.01 403.0
335
469
2 hours
98 401.6 26.53 401.0
336
463
4 hours
99 406.5 25.66 406.0
335
475
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
406.3
407.6
405.2
406.7
405.8
26.61
26.55
25.54
24.33
23.60
405.0
405.0
403.0
405.0
403.0
352
346
347
352
344
484
484
474
473
468
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
405.4
407.8
404.1
406.9
405.5
23.09
24.89
25.16
24.84
22.53
400.5
408.0
406.0
408.0
406.0
350
360
344
339
361
483
484
476
462
465
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
406.5
406.1
402.9
402.9
404.5
23.58
23.82
24.89
25.66
25.90
408.0
407.5
401.0
402.5
405.0
351
346
355
335
327
467
467
477
467
464
CONFIDENTIAL
681
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 23 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
25mcg
101 Day 1
Pre-dose
101 405.0 23.55 408.0
330
471
(Bazetts) (msec)
10 mins
98 405.6 27.83 405.5
322
469
1 hour
100 400.4 25.68 401.5
326
472
2 hours
100 401.0 23.32 402.0
349
457
4 hours
101 401.9 21.30 403.0
344
465
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
405.2
408.2
404.5
405.0
406.7
27.09
26.30
23.31
25.99
25.88
407.0
409.0
404.0
404.0
406.0
337
348
349
352
333
469
482
464
480
470
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
408.3
409.6
408.1
408.2
405.9
25.30
24.38
23.64
22.91
23.47
409.0
411.0
403.0
406.0
409.0
323
346
352
360
357
475
485
471
510
481
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
405.5
409.6
403.0
402.5
405.9
24.97
25.54
24.11
25.06
28.04
403.5
408.0
405.0
404.0
405.0
350
347
344
326
327
479
476
452
464
466
CONFIDENTIAL
682
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 24 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
50mcg
102 Day 1
Pre-dose
102 407.2 22.96 404.0
361
468
(Bazetts) (msec)
10 mins
102 411.0 26.19 412.0
351
487
1 hour
100 406.6 25.30 405.5
361
494
2 hours
101 407.9 22.94 409.0
361
482
4 hours
99 406.3 25.16 405.0
356
507
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
407.7
415.9
409.7
406.5
410.6
22.23
20.32
25.19
24.47
23.41
408.5
417.0
408.0
409.0
408.0
352
378
353
338
358
469
470
470
473
486
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
403.6
415.4
407.2
406.8
408.1
20.26
21.37
21.55
22.65
22.10
405.0
416.0
408.0
406.0
408.0
314
362
345
336
361
457
461
457
468
463
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
408.2
415.4
409.2
406.7
407.0
22.72
22.31
21.28
23.75
22.81
409.0
418.0
410.5
410.0
408.0
351
335
351
344
350
477
455
466
476
460
CONFIDENTIAL
683
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 25 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
Placebo
102 Day 1
Pre-dose
102 154.7 20.17 153.5
105
209
10 mins
102 157.1 21.31 154.0
111
211
1 hour
101 157.0 21.05 155.0
104
207
2 hours
101 156.8 21.25 156.0
110
229
4 hours
101 159.3 21.95 157.0
109
230
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
157.6
158.0
158.1
161.2
158.8
21.71
20.31
22.89
22.71
23.30
154.0
156.0
155.0
158.0
157.0
111
121
109
119
109
209
215
224
229
229
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
158.9
158.1
160.5
158.5
160.5
19.94
20.30
19.90
20.22
22.61
156.0
156.0
158.0
157.0
157.0
120
122
125
116
121
202
213
212
214
226
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
157.4
158.2
158.7
158.8
160.2
21.11
19.68
20.69
22.86
21.73
158.0
157.0
155.0
157.0
159.0
105
124
127
114
121
236
205
202
240
232
CONFIDENTIAL
684
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 26 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
3mcg
101 Day 1
Pre-dose
101 159.5 23.05 159.0
102
231
10 mins
97 161.7 25.49 159.0
111
246
1 hour
101 162.6 24.25 159.0
108
230
2 hours
101 162.7 23.98 165.0
88
229
4 hours
101 163.9 24.46 164.0
113
250
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
160.8
161.4
163.3
164.8
164.3
22.43
22.78
24.29
23.48
23.11
159.5
161.0
166.0
165.0
165.0
105
105
105
105
107
226
230
236
230
225
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
161.6
162.5
163.7
163.7
163.2
21.05
22.36
23.81
23.47
23.31
157.0
161.0
161.5
165.0
161.0
108
102
99
102
117
220
213
221
215
224
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
161.3
162.4
160.2
162.7
164.5
23.41
23.15
24.41
24.18
25.02
160.0
162.0
160.0
163.5
165.0
107
109
96
110
107
218
217
205
215
215
CONFIDENTIAL
685
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 27 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
6.25mcg
101 Day 1
Pre-dose
101 163.6 22.40 161.0
101
216
10 mins
100 165.0 24.33 163.5
103
225
1 hour
100 165.2 24.26 165.0
101
226
2 hours
101 166.3 26.22 167.0
97
235
4 hours
101 167.3 27.24 167.0
103
237
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
163.5
166.1
165.9
165.5
166.6
23.87
23.43
25.28
26.18
25.21
161.0
164.0
164.5
166.0
165.0
109
112
115
104
114
224
223
236
245
236
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
162.4
162.9
163.4
165.6
167.4
22.56
22.91
24.42
24.29
23.47
161.0
160.0
163.0
163.0
163.5
111
98
107
120
111
218
216
225
239
233
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
162.8
163.6
164.6
164.1
165.2
21.27
23.11
20.59
22.51
23.38
160.0
164.0
163.0
165.0
163.5
112
112
114
104
108
219
228
218
230
230
CONFIDENTIAL
686
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 28 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
12.5mcg
100 Day 1
Pre-dose
100 159.3 21.67 157.0
109
225
10 mins
99 161.0 21.63 159.0
104
229
1 hour
98 159.8 22.53 158.0
111
226
2 hours
98 162.9 23.63 160.0
105
238
4 hours
99 163.6 23.10 161.0
105
244
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
159.7
160.8
162.0
163.2
163.5
23.04
21.23
20.53
23.78
22.49
159.0
157.0
162.0
160.0
161.0
110
111
109
115
112
229
234
221
259
234
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
158.6
159.5
161.7
162.7
162.9
22.82
21.79
21.38
20.82
21.76
154.5
157.0
158.0
161.0
162.0
108
105
110
110
110
250
234
231
224
226
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
161.0
161.0
160.5
163.4
162.4
23.23
23.23
24.14
25.08
25.37
156.0
157.0
157.5
159.0
161.5
112
118
114
105
97
238
238
233
249
238
CONFIDENTIAL
687
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 29 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
25mcg
101 Day 1
Pre-dose
101 159.8 23.01 158.0
108
228
10 mins
98 159.8 23.31 158.5
104
238
1 hour
100 160.4 23.79 159.5
106
250
2 hours
100 161.8 24.22 161.0
102
244
4 hours
101 162.6 24.07 164.0
103
251
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
159.4
159.2
161.6
162.7
163.4
20.86
23.57
23.15
22.95
23.95
159.0
162.0
161.5
164.0
163.0
111
106
107
106
115
210
214
224
221
219
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
157.2
158.0
159.7
160.8
160.9
22.05
21.05
21.96
22.66
22.49
154.0
157.0
159.0
161.0
161.0
101
112
95
97
90
225
237
209
215
230
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
158.0
156.8
158.4
159.4
162.2
22.26
21.92
23.33
22.72
24.97
157.0
155.0
155.0
157.0
159.0
112
111
107
108
107
213
208
235
228
237
CONFIDENTIAL
688
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 30 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
50mcg
102 Day 1
Pre-dose
102 158.5 20.29 156.0
110
214
10 mins
102 158.9 18.91 158.5
114
227
1 hour
100 160.2 20.11 160.0
122
233
2 hours
101 161.3 20.34 162.0
121
239
4 hours
99 163.1 21.19 164.0
118
239
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
158.5
156.9
160.1
162.6
161.9
19.81
21.11
21.03
20.43
21.75
156.5
156.0
159.0
163.0
163.0
120
116
120
131
121
220
219
235
236
225
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
158.1
156.8
160.6
160.6
161.5
19.30
19.45
18.95
19.41
18.58
156.0
154.0
160.0
158.0
160.0
119
121
124
121
122
204
215
214
223
229
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
159.3
158.4
158.1
159.7
161.8
21.39
20.45
21.65
20.79
22.09
158.5
159.0
157.5
160.0
159.0
122
121
121
121
121
214
212
226
216
234
CONFIDENTIAL
689
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 31 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) Placebo
102 Day 1
Pre-dose
102
83.4
9.87
84.0
63
112
10 mins
102
83.5
9.79
83.5
64
108
1 hour
101
83.7
9.60
85.0
63
105
2 hours
101
83.5
9.77
82.0
63
112
4 hours
101
83.5 10.01
83.0
57
107
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
83.0
81.7
83.1
83.0
82.3
10.60
11.36
10.87
10.80
11.84
82.0
82.0
83.0
82.0
83.0
51
53
54
52
51
118
116
118
124
117
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
90
90
88
82.4
83.9
83.6
83.5
83.0
9.69
10.31
10.47
10.69
10.47
82.5
85.0
84.0
83.0
83.5
59
54
53
60
56
110
115
112
117
108
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
85
87
87
86
81.5
82.8
82.7
82.7
83.9
10.85
9.82
10.91
11.25
10.74
81.0
83.0
84.0
84.0
84.0
58
62
60
55
60
115
111
108
113
116
CONFIDENTIAL
690
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 32 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 3mcg
101 Day 1
Pre-dose
101
84.3
9.55
86.0
56
106
10 mins
97
84.6
9.75
85.0
51
102
1 hour
101
84.5 10.27
85.0
55
109
2 hours
101
86.0
9.85
85.0
64
124
4 hours
101
86.8 10.30
86.0
57
132
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
91
93
93
93
84.3
85.3
85.8
85.5
85.9
11.48
12.25
11.47
11.11
11.49
84.0
86.0
86.0
85.0
86.0
56
57
55
62
56
129
136
133
136
135
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
85
86
86
86
84.8
84.0
85.1
85.8
85.3
11.83
11.43
11.24
12.04
11.89
85.5
84.0
86.0
87.0
85.0
57
57
56
50
50
137
138
134
141
137
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
83
84
84
84
83.7
82.6
83.6
83.7
84.0
11.47
11.58
11.35
11.54
10.70
83.0
83.0
83.0
84.0
82.5
58
59
62
56
60
144
140
130
131
130
CONFIDENTIAL
691
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 33 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 6.25mcg
101 Day 1
Pre-dose
101
85.7 12.59
85.0
58
141
10 mins
100
86.0 11.48
86.0
61
136
1 hour
100
85.8 12.26
83.0
61
139
2 hours
101
86.6 11.49
85.0
62
138
4 hours
101
86.3 12.35
85.0
63
136
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
97
97
84.2
84.3
84.4
85.1
85.2
10.48
10.47
10.40
10.18
10.37
85.0
86.0
84.0
85.0
86.0
56
54
53
56
59
100
103
100
100
101
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
93
93
93
92
83.9
83.8
84.7
84.6
85.3
9.16
9.35
9.80
9.83
8.84
84.0
84.0
86.0
86.0
86.5
62
63
61
65
64
100
100
100
100
100
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
91
90
91
91
90
84.3
84.7
83.9
84.2
84.8
9.69
9.78
10.86
10.13
9.89
84.0
85.0
84.0
84.0
84.5
60
55
46
61
61
100
100
102
101
101
CONFIDENTIAL
692
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 34 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 12.5mcg
100 Day 1
Pre-dose
100
84.2
9.52
83.0
62
112
10 mins
99
84.1 10.10
83.0
63
114
1 hour
98
83.6 11.24
83.0
61
127
2 hours
98
84.5 10.51
83.5
65
125
4 hours
99
85.4 10.84
85.0
63
132
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
95
95
94
83.5
84.2
85.2
85.6
85.0
10.87
10.08
9.05
10.91
10.47
84.0
85.0
85.0
85.0
85.0
60
61
66
60
62
124
120
109
126
117
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
91
91
91
83.9
83.8
83.8
85.0
84.9
10.95
11.01
10.83
10.53
10.96
84.0
84.0
83.0
85.0
84.0
59
58
61
60
59
120
118
118
121
133
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
88
88
88
88
83.5
83.5
83.8
83.9
84.8
8.82
9.13
9.72
9.45
8.83
83.0
83.5
84.0
85.0
85.0
60
59
59
59
61
100
101
103
100
100
CONFIDENTIAL
693
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 35 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 25mcg
101 Day 1
Pre-dose
101
82.6 11.00
83.0
56
111
10 mins
98
83.3 11.32
84.0
52
115
1 hour
100
82.5 11.14
83.0
55
117
2 hours
100
82.4 11.28
82.0
51
105
4 hours
101
83.1 10.88
82.0
58
111
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
95
96
96
95
82.4
82.2
82.4
83.3
83.4
11.09
11.16
11.43
11.65
11.31
82.0
82.0
81.5
82.0
82.0
58
55
51
55
55
108
107
106
112
116
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
92
93
93
93
82.9
82.5
83.8
83.5
84.1
10.26
10.97
10.81
10.13
11.30
82.0
82.0
84.0
84.0
84.0
56
49
59
59
48
104
109
111
105
113
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
93
93
93
93
82.1
83.5
82.6
83.4
83.7
11.13
11.45
11.05
11.02
12.03
83.0
84.0
83.0
84.0
85.0
58
56
51
58
51
111
114
107
115
115
CONFIDENTIAL
694
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 36 of 36
Table 8.38
Summary of ECG Values
Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 50mcg
102 Day 1
Pre-dose
102
83.4
8.96
84.0
55
106
10 mins
102
84.0 10.01
85.0
50
106
1 hour
100
83.7 10.36
85.0
53
106
2 hours
101
84.2
9.22
85.0
54
107
4 hours
99
83.6
9.38
84.0
51
107
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
100
99
99
98
84.1
84.2
84.7
85.6
85.4
9.03
9.03
9.61
8.43
8.91
86.0
85.0
85.0
87.0
87.0
59
59
56
55
60
101
101
100
101
101
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
96
97
97
97
84.2
84.6
84.3
84.8
85.0
8.62
9.03
9.07
9.33
10.19
85.0
85.0
86.0
86.0
87.0
59
59
55
59
59
100
100
99
100
109
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
98
95
98
97
97
82.5
82.7
83.5
83.6
84.1
10.22
10.72
11.03
9.98
9.51
84.0
84.0
85.0
85.0
85.0
59
57
56
56
56
108
108
106
102
103
CONFIDENTIAL
695
Day 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any time post-baseline
n
102
101
101
100
101
102
Normal
49 (48%)
38 (38%)
41 (41%)
50 (50%)
42 (42%)
50 (49%)
Abnormal - not clinically
45 (44%)
51 (50%)
54 (53%)
40 (40%)
47 (47%)
45 (44%)
significant
Abnormal - clinically significant
8
(8%)
12 (12%)
6
(6%)
10 (10%)
12 (12%)
7
(7%)
Not available
0
0
0
0
0
0
102
1
(<1%)
101
0
101
0
100
0
101
0
102
0
18
(18%)
19
(19%)
17
(17%)
17
(17%)
18
(18%)
17
(17%)
77
6
0
(75%)
(6%)
79
3
0
(78%)
(3%)
80
4
0
(79%)
(4%)
81
2
0
(81%)
(2%)
76
7
0
(75%)
(7%)
82
3
0
(80%)
(3%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
696
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
Pre-dose
n
102
101
101
100
101
102
Normal
82 (80%)
78 (77%)
78 (77%)
81 (81%)
83 (82%)
87 (85%)
Abnormal - not clinically
16 (16%)
18 (18%)
17 (17%)
16 (16%)
14 (14%)
12 (12%)
significant
Abnormal - clinically significant
3
(3%)
2
(2%)
5
(5%)
2
(2%)
2
(2%)
1 (<1%)
Not available
1 (<1%)
3
(3%)
1 (<1%)
1
(1%)
2
(2%)
2
(2%)
102
0
101
0
101
0
100
0
101
0
102
0
0
102 (100%)
0
0
101 (100%)
0
0
101 (100%)
0
0
100 (100%)
0
0
101 (100%)
0
0
102 (100%)
0
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
697
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
10 mins
n
102
97
100
99
98
102
Normal
80 (78%)
73 (75%)
80 (80%)
79 (80%)
78 (80%)
88 (86%)
Abnormal - not clinically
13 (13%)
19 (20%)
16 (16%)
17 (17%)
17 (17%)
13 (13%)
significant
Abnormal - clinically significant
5
(5%)
4
(4%)
4
(4%)
1
(1%)
2
(2%)
1 (<1%)
Not available
4
(4%)
1
(1%)
0
2
(2%)
1
(1%)
0
102
3
(3%)
97
2
(2%)
100
1
(1%)
99
0
(2%)
(3%)
(3%)
74
23
0
(73%)
(23%)
70
22
0
(72%)
(23%)
73
23
0
(73%)
(23%)
80
18
0
98
0
102
3
(3%)
(1%)
(2%)
(81%)
(18%)
81
17
0
80
17
0
(78%)
(17%)
(83%)
(17%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
698
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
1 hour
n
101
101
100
98
100
100
Normal
77 (76%)
71 (70%)
76 (76%)
76 (78%)
79 (79%)
86 (86%)
Abnormal - not clinically
18 (18%)
25 (25%)
18 (18%)
18 (18%)
15 (15%)
12 (12%)
significant
Abnormal - clinically significant
4
(4%)
4
(4%)
4
(4%)
2
(2%)
5
(5%)
2
(2%)
Not available
2
(2%)
1 (<1%)
2
(2%)
2
(2%)
1
(1%)
0
101
2
(2%)
101
4
(4%)
100
0
98
0
(3%)
(6%)
(6%)
76
20
0
(75%)
(20%)
72
19
0
(71%)
(19%)
74
20
0
(74%)
(20%)
82
14
0
100
1
(1%)
100
1
(2%)
(3%)
(84%)
(14%)
78
18
0
(78%)
(18%)
82
17
0
(1%)
(82%)
(17%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
699
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
2 hours
n
101
101
101
98
100
101
Normal
78 (77%)
74 (73%)
72 (71%)
78 (80%)
79 (79%)
86 (85%)
Abnormal - not clinically
16 (16%)
23 (23%)
23 (23%)
17 (17%)
19 (19%)
14 (14%)
significant
Abnormal - clinically significant
5
(5%)
3
(3%)
4
(4%)
1
(1%)
2
(2%)
1 (<1%)
Not available
2
(2%)
1 (<1%)
2
(2%)
2
(2%)
0
0
101
1
(<1%)
101
3
(3%)
101
3
(3%)
98
0
(<1%)
(8%)
(4%)
81
18
0
(80%)
(18%)
71
19
0
(70%)
(19%)
71
23
0
(70%)
(23%)
84
12
0
100
1
(1%)
101
1
(<1%)
(2%)
(3%)
(<1%)
(86%)
(12%)
76
20
0
(76%)
(20%)
84
15
0
(83%)
(15%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
700
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
4 hours
n
101
101
101
99
101
99
Normal
79 (78%)
78 (77%)
72 (71%)
70 (71%)
77 (76%)
76 (77%)
Abnormal - not clinically
16 (16%)
16 (16%)
25 (25%)
26 (26%)
19 (19%)
20 (20%)
significant
Abnormal - clinically significant
4
(4%)
6
(6%)
3
(3%)
2
(2%)
2
(2%)
1
(1%)
Not available
2
(2%)
1 (<1%)
1 (<1%)
1
(1%)
3
(3%)
2
(2%)
101
2
(2%)
101
4
(4%)
101
4
(4%)
99
0
(3%)
(6%)
(5%)
77
19
0
(76%)
(19%)
71
20
0
(70%)
(20%)
70
22
0
(69%)
(22%)
81
14
0
101
2
(2%)
99
1
(1%)
(4%)
(2%)
(4%)
(82%)
(14%)
75
22
0
(74%)
(22%)
79
15
0
(80%)
(15%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
701
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
Pre-dose
n
95
98
99
97
99
100
Normal
81 (85%)
77 (79%)
77 (78%)
75 (77%)
84 (85%)
88 (88%)
Abnormal - not clinically
10 (11%)
16 (16%)
18 (18%)
19 (20%)
13 (13%)
10 (10%)
significant
Abnormal - clinically significant
2
(2%)
4
(4%)
2
(2%)
2
(2%)
2
(2%)
1
(1%)
Not available
2
(2%)
1
(1%)
2
(2%)
1
(1%)
0
1
(1%)
95
2
(2%)
98
0
99
0
(1%)
(2%)
64
28
0
(67%)
(29%)
70
26
0
(71%)
(27%)
68
29
0
97
2
(2%)
99
2
(2%)
100
3
(3%)
(2%)
(3%)
(2%)
(2%)
(69%)
(29%)
67
25
0
(69%)
(26%)
63
32
0
(64%)
(32%)
60
35
0
(60%)
(35%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
702
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
10 mins
n
92
91
95
96
95
100
Normal
75 (82%)
71 (78%)
73 (77%)
78 (81%)
83 (87%)
86 (86%)
Abnormal - not clinically
14 (15%)
16 (18%)
18 (19%)
16 (17%)
8
(8%)
12 (12%)
significant
Abnormal - clinically significant
0
2
(2%)
1
(1%)
2
(2%)
3
(3%)
2
(2%)
Not available
3
(3%)
2
(2%)
3
(3%)
0
1
(1%)
0
92
1
(1%)
91
2
(2%)
95
0
(2%)
(2%)
81
8
0
(88%)
(9%)
77
10
0
(85%)
(11%)
80
14
0
96
1
(1%)
95
3
(3%)
100
0
(1%)
(2%)
(2%)
(2%)
(84%)
(15%)
84
9
0
(88%)
(9%)
79
11
0
(83%)
(12%)
86
12
0
(86%)
(12%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
703
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
1 hour
n
93
93
96
95
96
99
Normal
77 (83%)
73 (78%)
69 (72%)
78 (82%)
83 (86%)
87 (88%)
Abnormal - not clinically
10 (11%)
16 (17%)
23 (24%)
14 (15%)
10 (10%)
12 (12%)
significant
Abnormal - clinically significant
3
(3%)
3
(3%)
2
(2%)
2
(2%)
3
(3%)
0
Not available
3
(3%)
1
(1%)
2
(2%)
1
(1%)
0
0
93
2
(2%)
93
3
(3%)
96
2
(2%)
95
4
(4%)
96
3
(3%)
99
1
(1%)
(3%)
(2%)
(4%)
(1%)
(3%)
(2%)
77
11
0
(83%)
(12%)
77
11
0
(83%)
(12%)
74
16
0
(77%)
(17%)
81
9
0
(85%)
(9%)
81
9
0
(84%)
(9%)
85
11
0
(86%)
(11%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
704
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
2 hours
n
93
93
97
95
96
99
Normal
78 (84%)
75 (81%)
73 (75%)
75 (79%)
79 (82%)
81 (82%)
Abnormal - not clinically
12 (13%)
15 (16%)
21 (22%)
14 (15%)
12 (13%)
16 (16%)
significant
Abnormal - clinically significant
2
(2%)
2
(2%)
2
(2%)
4
(4%)
4
(4%)
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
2
(2%)
1
(1%)
1
(1%)
93
3
(3%)
93
2
(3%)
76
11
0
(82%)
(12%)
83
8
0
(2%)
(89%)
(9%)
97
1
(1%)
95
2
(2%)
96
3
(3%)
99
1
(1%)
(5%)
(1%)
(2%)
(4%)
76
15
0
(78%)
(15%)
82
10
0
(86%)
(11%)
80
11
0
(83%)
(11%)
82
12
0
(83%)
(12%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
705
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
4 hours
n
93
93
97
94
95
98
Normal
77 (83%)
74 (80%)
75 (77%)
75 (80%)
76 (80%)
84 (86%)
Abnormal - not clinically
13 (14%)
15 (16%)
22 (23%)
14 (15%)
11 (12%)
13 (13%)
significant
Abnormal - clinically significant
3
(3%)
3
(3%)
0
3
(3%)
5
(5%)
0
Not available
0
1
(1%)
0
2
(2%)
3
(3%)
1
(1%)
93
2
(2%)
93
1
(1%)
97
2
(2%)
94
2
(2%)
95
3
(3%)
98
1
(1%)
(3%)
(2%)
(1%)
(1%)
(6%)
(3%)
80
8
0
(86%)
(9%)
78
12
0
(84%)
(13%)
81
13
0
(84%)
(13%)
81
10
0
(86%)
(11%)
72
14
0
(76%)
(15%)
81
13
0
(83%)
(13%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
706
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
Pre-dose
n
92
92
95
92
95
97
Normal
81 (88%)
71 (77%)
78 (82%)
78 (85%)
79 (83%)
86 (89%)
Abnormal - not clinically
10 (11%)
19 (21%)
16 (17%)
12 (13%)
13 (14%)
7
(7%)
significant
Abnormal - clinically significant
1
(1%)
2
(2%)
0
1
(1%)
1
(1%)
0
Not available
0
0
1
(1%)
1
(1%)
2
(2%)
4
(4%)
92
3
(3%)
0
69
20
0
(75%)
(22%)
92
0
95
2
(1%)
69
22
0
(75%)
(24%)
67
26
0
(2%)
92
1
(1%)
0
(71%)
(27%)
71
20
0
95
1
(1%)
0
(77%)
(22%)
70
24
0
97
3
(3%)
0
(74%)
(25%)
72
22
0
(74%)
(23%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
707
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
10 mins
n
91
85
93
91
92
96
Normal
78 (86%)
66 (78%)
74 (80%)
78 (86%)
78 (85%)
83 (86%)
Abnormal - not clinically
11 (12%)
17 (20%)
18 (19%)
11 (12%)
12 (13%)
11 (11%)
significant
Abnormal - clinically significant
1
(1%)
1
(1%)
0
2
(2%)
0
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
0
2
(2%)
1
(1%)
91
0
85
0
93
1
(1%)
91
0
92
2
(2%)
(1%)
(2%)
(1%)
81
8
0
(89%)
(9%)
80
4
0
(94%)
(5%)
76
14
0
(82%)
(15%)
86
4
0
(95%)
(4%)
74
16
0
(2%)
(80%)
(17%)
96
0
2
(2%)
80
14
0
(83%)
(15%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
708
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
1 hour
n
90
86
93
91
93
97
Normal
74 (82%)
66 (77%)
76 (82%)
75 (82%)
82 (88%)
83 (86%)
Abnormal - not clinically
13 (14%)
17 (20%)
17 (18%)
13 (14%)
9 (10%)
12 (12%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
2
(2%)
1
(1%)
0
Not available
1
(1%)
2
(2%)
0
1
(1%)
1
(1%)
2
(2%)
90
0
86
0
93
2
(2%)
91
0
93
2
(2%)
(1%)
(1%)
(2%)
79
9
0
(88%)
(10%)
80
5
0
(93%)
(6%)
80
10
0
(86%)
(11%)
85
4
0
(93%)
(4%)
72
19
0
(2%)
97
1
(1%)
0
(77%)
(20%)
82
14
0
(85%)
(14%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
709
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
2 hours
n
90
86
93
91
93
97
Normal
73 (81%)
67 (78%)
73 (78%)
76 (84%)
79 (85%)
78 (80%)
Abnormal - not clinically
15 (17%)
18 (21%)
20 (22%)
13 (14%)
9 (10%)
17 (18%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
1
(1%)
2
(2%)
0
Not available
0
0
0
1
(1%)
3
(3%)
2
(2%)
90
0
86
0
93
3
(3%)
91
1
(1%)
93
1
(1%)
97
0
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
83
6
0
(92%)
(7%)
78
7
0
(91%)
(8%)
77
12
0
(83%)
(13%)
84
5
0
(92%)
(5%)
73
18
0
(78%)
(19%)
83
13
0
(86%)
(13%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
710
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
4 hours
n
88
86
92
91
93
97
Normal
74 (84%)
67 (78%)
73 (79%)
78 (86%)
77 (83%)
86 (89%)
Abnormal - not clinically
13 (15%)
18 (21%)
19 (21%)
12 (13%)
15 (16%)
10 (10%)
significant
Abnormal - clinically significant
1
(1%)
1
(1%)
0
1
(1%)
1
(1%)
0
Not available
0
0
0
0
0
1
(1%)
88
0
86
1
(1%)
79
8
0
(90%)
(9%)
80
5
0
(1%)
(93%)
(6%)
92
1
(1%)
91
1
(1%)
93
1
(2%)
(1%)
79
10
0
(86%)
(11%)
86
3
0
(95%)
(3%)
74
18
0
(1%)
(80%)
(19%)
97
1
(1%)
(2%)
81
13
0
(84%)
(13%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
711
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 17 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
Pre-dose
n
89
87
91
89
94
98
Normal
76 (85%)
68 (78%)
74 (81%)
76 (85%)
77 (82%)
85 (87%)
Abnormal - not clinically
10 (11%)
18 (21%)
17 (19%)
12 (13%)
13 (14%)
10 (10%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
1
(1%)
4
(4%)
1
(1%)
Not available
1
(1%)
0
0
0
0
2
(2%)
89
1
(1%)
87
1
(1%)
91
1
(1%)
(2%)
69
18
0
(78%)
(20%)
68
16
0
(78%)
(18%)
68
22
0
(1%)
89
1
(1%)
0
(75%)
(24%)
75
13
0
(84%)
(15%)
94
0
98
2
(2%)
(3%)
(1%)
75
16
0
(80%)
(17%)
77
18
0
(79%)
(18%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
712
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 18 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
10 mins
n
85
83
90
88
93
95
Normal
76 (89%)
67 (81%)
72 (80%)
76 (86%)
70 (75%)
79 (83%)
Abnormal - not clinically
7
(8%)
13 (16%)
17 (19%)
10 (11%)
17 (18%)
12 (13%)
significant
Abnormal - clinically significant
1
(1%)
3
(4%)
0
1
(1%)
5
(5%)
2
(2%)
Not available
1
(1%)
0
1
(1%)
1
(1%)
1
(1%)
2
(2%)
85
2
(2%)
0
72
11
0
(85%)
(13%)
83
1
(1%)
90
0
88
0
93
0
95
0
(2%)
(2%)
74
6
0
(89%)
(7%)
79
11
0
84
9
0
(88%)
(9%)
(88%)
(12%)
81
7
0
(92%)
(8%)
80
13
0
(86%)
(14%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
713
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 19 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
1 hour
n
87
84
91
88
93
98
Normal
75 (86%)
63 (75%)
76 (84%)
71 (81%)
77 (83%)
83 (85%)
Abnormal - not clinically
10 (11%)
18 (21%)
14 (15%)
13 (15%)
13 (14%)
12 (12%)
significant
Abnormal - clinically significant
1
(1%)
2
(2%)
0
1
(1%)
2
(2%)
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
3
(3%)
1
(1%)
2
(2%)
87
2
(2%)
0
74
11
0
(85%)
(13%)
84
0
91
0
88
0
93
1
(2%)
73
9
0
(87%)
(11%)
81
10
0
(89%)
(11%)
80
8
0
(91%)
(9%)
83
9
0
(1%)
(89%)
(10%)
98
0
1
(1%)
88
9
0
(90%)
(9%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
714
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 20 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
2 hours
n
87
84
91
88
93
97
Normal
70 (80%)
66 (79%)
75 (82%)
71 (81%)
75 (81%)
82 (85%)
Abnormal - not clinically
15 (17%)
15 (18%)
15 (16%)
13 (15%)
15 (16%)
13 (13%)
significant
Abnormal - clinically significant
1
(1%)
3
(4%)
0
1
(1%)
3
(3%)
1
(1%)
Not available
1
(1%)
0
1
(1%)
3
(3%)
0
1
(1%)
87
0
84
1
(1%)
91
0
88
0
93
2
(2%)
97
1
(1%)
(3%)
(4%)
(1%)
(2%)
(3%)
(2%)
74
10
0
(85%)
(11%)
73
7
0
(87%)
(8%)
76
14
0
(84%)
(15%)
77
9
0
(88%)
(10%)
80
8
0
(86%)
(9%)
83
11
0
(86%)
(11%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
715
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 21 of 21
Table 8.39
Summary of ECG Findings
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
4 hours
n
86
84
90
88
93
97
Normal
72 (84%)
61 (73%)
68 (76%)
73 (83%)
75 (81%)
83 (86%)
Abnormal - not clinically
12 (14%)
17 (20%)
20 (22%)
13 (15%)
16 (17%)
12 (12%)
significant
Abnormal - clinically significant
2
(2%)
4
(5%)
0
1
(1%)
2
(2%)
0
Not available
0
2
(2%)
2
(2%)
1
(1%)
0
2
(2%)
86
1
(1%)
84
1
(1%)
90
1
(1%)
88
0
93
1
(1%)
(2%)
(2%)
(2%)
76
8
0
(88%)
(9%)
70
11
0
(83%)
(13%)
75
12
0
(83%)
(13%)
79
7
0
(90%)
(8%)
85
7
0
(1%)
(91%)
(8%)
97
1
(1%)
(2%)
82
12
0
(85%)
(12%)
YM2008/00019/00
B2C109575
Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.
CONFIDENTIAL
716
n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.40
Summary of Maximum Post-Dose QTc(F) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
<= 450 102 (100%)
98 (97%)
100 (>99%)
96 (96%)
101 (100%)
100 (98%)
450 < - <= 480
0
3
(3%)
1 (<1%)
4
(4%)
0
1 (<1%)
480 < - <= 500
0
0
0
0
0
1 (<1%)
> 500
0
0
0
0
0
0
717
<=
450 < - <=
480 < - <=
>
Day 14
n
<=
450 < - <=
480 < - <=
>
Day 28
n
93
93 (100%)
0
0
0
93
92
1
0
0
450
480
500
500
91
91 (100%)
0
0
0
86
85
1
0
0
450
480
500
500
87
85
2
0
0
85
84
1
0
0
(98%)
(2%)
(99%)
(1%)
(99%)
(1%)
(99%)
(1%)
97
95
2
0
0
93
92
1
0
0
(98%)
(2%)
(99%)
(1%)
91
91 (100%)
0
0
0
96
92
4
0
0
91
88
3
0
0
88
85
3
0
0
(96%)
(4%)
(97%)
(3%)
(97%)
(3%)
96
91
5
0
0
94
93
1
0
0
93
90
3
0
0
(95%)
(5%)
(99%)
(1%)
(97%)
(3%)
100
99
0
1
0
97
96
1
0
0
98
94
4
0
0
(99%)
(1%)
(99%)
(1%)
(96%)
(4%)
YM2008/00019/00
B2C109575
<=
450 < - <=
480 < - <=
>
450
480
500
500
CONFIDENTIAL
Day 7
n
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.41
Summary of Maximum Post-Dose QTc(B) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
<= 450
95 (93%)
94 (93%)
96 (95%)
95 (95%)
94 (93%)
92 (90%)
450 < - <= 480
7 (7%)
6 (6%)
5 (5%)
5 (5%)
7 (7%)
7 (7%)
480 < - <= 500
0
1 (<1%)
0
0
0
2 (2%)
> 500
0
0
0
0
0
1 (<1%)
718
<=
450 < - <=
480 < - <=
>
Day 14
n
<=
450 < - <=
480 < - <=
>
Day 28
n
93
86 (92%)
7 (8%)
0
0
93
87 (94%)
6 (6%)
0
0
97
92 (95%)
5 (5%)
0
0
96
88 (92%)
7 (7%)
1 (1%)
0
96
88 (92%)
6 (6%)
2 (2%)
0
100
90 (90%)
9 (9%)
1 (1%)
0
450
480
500
500
91
86 (95%)
5 (5%)
0
0
86
78 (91%)
8 (9%)
0
0
93
85 (91%)
8 (9%)
0
0
91
84 (92%)
6 (7%)
1 (1%)
0
94
83 (88%)
9 (10%)
1 (1%)
1 (1%)
97
87 (90%)
10 (10%)
0
0
450
480
500
500
87
80 (92%)
6 (7%)
1 (1%)
0
85
81 (95%)
4 (5%)
0
0
91
89 (98%)
2 (2%)
0
0
88
81 (92%)
7 (8%)
0
0
93
84 (90%)
9 (10%)
0
0
98
90 (92%)
8 (8%)
0
0
YM2008/00019/00
B2C109575
<=
450 < - <=
480 < - <=
>
450
480
500
500
CONFIDENTIAL
Day 7
n
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.42
Summary of Maximum Change From Baseline (0-4 hours) in QTc(F) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
< -60
0
0
0
0
0
0
-60 <= - < -30
0
0
0
1 (1%)
0
0
-30 <= - <
0
20 (20%)
23 (23%)
20 (20%)
18 (18%)
18 (18%)
14 (14%)
0 <= - < 30
72 (71%)
66 (65%)
73 (72%)
74 (74%)
75 (74%)
81 (79%)
30 <= - < 60
10 (10%)
10 (10%)
7 (7%)
5 (5%)
8 (8%)
7 (7%)
>= 60
0
2 (2%)
1 (<1%)
2 (2%)
0
0
719
-60
-30
0
30
<=
<=
<=
<=
93
0
1 (1%)
23 (25%)
56 (60%)
13 (14%)
0
93
0
1 (1%)
13 (14%)
65 (70%)
13 (14%)
1 (1%)
97
0
2 (2%)
31 (32%)
55 (57%)
9 (9%)
0
96
0
1 (1%)
21 (22%)
62 (65%)
10 (10%)
2 (2%)
96
0
0
28 (29%)
58 (60%)
9 (9%)
1 (1%)
100
0
0
20 (20%)
63 (63%)
17 (17%)
0
< -60
< -30
<
0
< 30
< 60
>= 60
91
0
1 (1%)
14 (15%)
66 (73%)
10 (11%)
0
86
0
2 (2%)
15 (17%)
59 (69%)
9 (10%)
1 (1%)
93
0
1 (1%)
28 (30%)
56 (60%)
8 (9%)
0
91
0
1 (1%)
21 (23%)
62 (68%)
7 (8%)
0
94
0
0
20 (21%)
64 (68%)
10 (11%)
0
97
0
0
16 (16%)
73 (75%)
8 (8%)
0
Day 14
n
-60
-30
0
30
<=
<=
<=
<=
YM2008/00019/00
B2C109575
< -60
< -30
<
0
< 30
< 60
>= 60
CONFIDENTIAL
Day 7
n
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.42
Summary of Maximum Change From Baseline (0-4 hours) in QTc(F) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 28
n
87
85
91
88
93
98
< -60
0
0
0
0
0
0
-60 <= - < -30
0
1 (1%)
1 (1%)
1 (1%)
1 (1%)
0
-30 <= - <
0
19 (22%)
23 (27%)
23 (25%)
15 (17%)
23 (25%)
18 (18%)
0 <= - < 30
53 (61%)
50 (59%)
55 (60%)
64 (73%)
54 (58%)
65 (66%)
30 <= - < 60
15 (17%)
10 (12%)
12 (13%)
7 (8%)
15 (16%)
15 (15%)
>= 60
0
1 (1%)
0
1 (1%)
0
0
CONFIDENTIAL
720
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.43
Summary of Maximum Change From Baseline (0-4 hours) in QTc(B) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
< -60
0
0
0
0
0
0
-60 <= - < -30
3 (3%)
0
0
1 (1%)
1 (<1%)
0
-30 <= - <
0
23 (23%)
30 (30%)
30 (30%)
27 (27%)
26 (26%)
19 (19%)
0 <= - < 30
66 (65%)
55 (54%)
59 (58%)
56 (56%)
61 (60%)
69 (68%)
30 <= - < 60
10 (10%)
14 (14%)
11 (11%)
15 (15%)
13 (13%)
14 (14%)
>= 60
0
2 (2%)
1 (<1%)
1 (1%)
0
0
721
-60
-30
0
30
<=
<=
<=
<=
93
0
2 (2%)
26 (28%)
46 (49%)
19 (20%)
0
93
0
1 (1%)
16 (17%)
60 (65%)
14 (15%)
2 (2%)
97
0
4 (4%)
25 (26%)
55 (57%)
13 (13%)
0
96
0
1 (1%)
23 (24%)
55 (57%)
14 (15%)
3 (3%)
96
0
0
25 (26%)
53 (55%)
15 (16%)
3 (3%)
100
0
1 (1%)
15 (15%)
56 (56%)
27 (27%)
1 (1%)
< -60
< -30
<
0
< 30
< 60
>= 60
91
0
2 (2%)
22 (24%)
53 (58%)
13 (14%)
1 (1%)
86
0
2 (2%)
19 (22%)
47 (55%)
17 (20%)
1 (1%)
93
1 (1%)
2 (2%)
28 (30%)
40 (43%)
22 (24%)
0
91
0
2 (2%)
19 (21%)
52 (57%)
18 (20%)
0
94
0
0
22 (23%)
52 (55%)
20 (21%)
0
97
0
0
12 (12%)
61 (63%)
23 (24%)
1 (1%)
Day 14
n
-60
-30
0
30
<=
<=
<=
<=
YM2008/00019/00
B2C109575
< -60
< -30
<
0
< 30
< 60
>= 60
CONFIDENTIAL
Day 7
n
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.43
Summary of Maximum Change From Baseline (0-4 hours) in QTc(B) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 28
n
87
85
91
88
93
98
< -60
0
0
1 (1%)
0
0
0
-60 <= - < -30
2 (2%)
4 (5%)
1 (1%)
3 (3%)
1 (1%)
0
-30 <= - <
0
17 (20%)
27 (32%)
27 (30%)
18 (20%)
22 (24%)
17 (17%)
0 <= - < 30
49 (56%)
39 (46%)
52 (57%)
54 (61%)
49 (53%)
55 (56%)
30 <= - < 60
18 (21%)
13 (15%)
9 (10%)
12 (14%)
20 (22%)
23 (23%)
>= 60
1 (1%)
2 (2%)
1 (1%)
1 (1%)
1 (1%)
3 (3%)
CONFIDENTIAL
722
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.44
Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc(F) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
101
99
Mean
0.8
0.8
0.9
2.0
0.0
1.9
SD
12.89
12.27
12.71
13.93
11.39
10.91
Median
1.3
-0.1
0.1
2.4
0.3
1.1
Min.
-41
-34
-42
-53
-31
-28
Max.
35
53
37
62
28
38
93
3.9
16.41
3.7
-46
72
97
-2.1
15.94
-0.7
-50
45
94
2.5
20.28
1.2
-68
103
95
-0.4
15.78
-0.4
-33
46
98
1.9
15.85
0.4
-59
38
Day 14
n
Mean
SD
Median
Min.
Max.
87
-0.3
15.58
-3.1
-38
42
86
1.8
18.28
0.4
-69
76
92
-3.0
17.22
-1.4
-71
39
91
0.4
16.87
2.3
-45
39
93
0.7
15.36
1.5
-38
49
96
-0.5
13.59
-1.2
-40
30
Day 28
n
Mean
SD
Median
Min.
Max.
86
1.8
15.50
1.4
-29
36
84
0.6
17.64
-2.3
-40
82
90
-0.9
16.99
1.1
-63
36
88
1.6
15.93
2.1
-39
57
93
1.6
18.06
-0.5
-60
46
97
2.2
15.62
1.0
-35
42
CONFIDENTIAL
93
1.8
16.37
0.9
-40
41
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
723
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.45
Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc(F) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 7
n
93
93
97
94
95
98
Mean
1.6
1.4
0.1
1.3
1.2
1.4
SD
10.92
11.57
11.29
10.84
12.52
11.52
Median
0.5
2.3
0.4
2.1
1.1
2.1
Min.
-29
-34
-31
-27
-32
-47
Max.
27
33
26
28
30
28
87
1.6
9.96
1.8
-31
25
86
-0.3
9.20
1.0
-26
19
92
-1.0
11.46
-0.9
-32
34
91
1.2
11.86
1.4
-40
32
93
0.5
11.00
0.2
-32
26
96
3.7
12.19
2.8
-21
76
Day 28
n
Mean
SD
Median
Min.
Max.
86
1.2
10.35
1.0
-25
26
84
-1.4
10.42
-0.8
-26
21
90
0.3
13.79
-0.5
-57
57
88
0.8
11.82
1.4
-26
40
93
1.9
11.13
3.1
-34
27
97
1.9
11.51
2.0
-28
31
CONFIDENTIAL
n
Mean
SD
Median
Min.
Max.
724
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.46
Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc(B) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
101
99
Mean
-3.3
-3.9
-3.6
-2.1
-3.1
0.3
SD
15.63
15.68
15.41
17.31
13.44
14.00
Median
-2.8
-4.4
-2.9
-1.5
-2.0
-0.3
Min.
-45
-39
-50
-87
-41
-33
Max.
38
56
32
61
28
46
93
1.9
18.96
1.3
-58
81
97
-2.9
19.11
-0.3
-64
44
94
0.8
23.04
-1.1
-85
92
95
-0.6
19.44
-3.7
-39
64
98
3.8
19.64
4.4
-61
43
Day 14
n
Mean
SD
Median
Min.
Max.
87
-1.7
18.57
-1.4
-46
38
86
0.4
21.02
-0.5
-86
90
92
-3.5
20.76
-1.6
-81
33
91
-0.5
19.96
0.3
-72
38
93
2.1
16.81
3.2
-34
44
96
2.3
17.64
1.7
-46
38
Day 28
n
Mean
SD
Median
Min.
Max.
86
-1.2
18.82
-1.9
-44
38
84
-3.4
21.47
-5.1
-46
94
90
-4.5
19.28
-3.1
-77
28
88
-2.3
18.19
-2.3
-53
58
93
-0.6
20.18
-1.7
-58
45
97
2.4
17.92
1.9
-36
52
CONFIDENTIAL
93
0.8
20.46
-0.4
-52
38
YM2008/00019/00
B2C109575
n
Mean
SD
Median
Min.
Max.
725
Day 7
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.47
Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc(B) Interval (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 7
n
93
93
97
94
95
98
Mean
0.2
-0.1
-2.0
-0.5
-0.4
1.6
SD
13.70
14.01
13.36
13.26
16.44
14.83
Median
-0.5
0.8
-1.8
0.8
0.1
3.0
Min.
-36
-46
-36
-36
-50
-50
Max.
34
33
38
27
40
37
87
0.3
13.56
1.5
-32
31
86
-2.6
13.07
-2.2
-36
28
92
-3.5
13.83
-4.3
-46
35
91
0.2
15.42
1.3
-48
39
93
-0.6
14.30
-1.4
-36
38
96
4.4
14.51
3.4
-28
81
Day 28
n
Mean
SD
Median
Min.
Max.
86
-2.4
13.42
-3.1
-44
36
84
-4.5
13.21
-4.6
-37
25
90
-3.5
16.68
-2.9
-64
54
88
-2.5
14.67
-2.6
-38
49
93
-0.8
14.88
0.2
-48
45
97
0.3
13.76
0.3
-39
31
CONFIDENTIAL
n
Mean
SD
Median
Min.
Max.
726
Day 14
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
97
100
99
98
102
LS Mean Change (SE) -1.0 (1.34)
0.2 (1.37)
2.7 (1.34)
1.7 (1.35)
1.4 (1.36)
3.1 (1.34)
Column vs Placebo
Difference
95% C.I.
p-value
1.3
(-2.5, 5.0)
0.516
3.7
(0.0, 7.4)
0.051
2.7
(-1.0, 6.5)
0.152
2.4
(-1.3, 6.2)
0.200
4.1
(0.4, 7.9)
0.030
CONFIDENTIAL
727
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
100
98
100
100
LS Mean Change (SE) -2.2 (1.43) -0.6 (1.43)
0.6 (1.44)
-0.4 (1.45)
-2.1 (1.43)
0.9 (1.44)
Column vs Placebo
Difference
95% C.I.
p-value
1.6
(-2.4, 5.6)
0.443
2.8
(-1.2, 6.7)
0.174
1.7
(-2.3, 5.7)
0.396
0.1
(-3.9, 4.0)
0.973
3.0
(-1.0, 7.1)
0.136
CONFIDENTIAL
728
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
98
100
101
LS Mean Change (SE)
1.1 (1.36)
0.9 (1.36)
0.5 (1.36)
1.5 (1.37)
-0.2 (1.36)
3.2 (1.36)
Column vs Placebo
Difference
95% C.I.
p-value
-0.2
(-4.0, 3.6)
0.910
-0.6
(-4.4, 3.2)
0.761
0.4
(-3.4, 4.2)
0.833
-1.3
(-5.0, 2.5)
0.509
2.2
(-1.6, 5.9)
0.266
CONFIDENTIAL
729
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
3.3 (1.48)
1.5 (1.48)
3.7 (1.48)
4.3 (1.49)
0.0 (1.47)
2.5 (1.49)
Column vs Placebo
Difference
95% C.I.
p-value
-1.8
(-6.0, 2.3)
0.384
0.4
(-3.7, 4.5)
0.854
1.0
(-3.1, 5.1)
0.630
-3.3
(-7.4, 0.8)
0.114
-0.8
(-5.0, 3.4)
0.704
CONFIDENTIAL
730
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
91
95
96
95
100
LS Mean Change (SE) -0.9 (1.70)
2.0 (1.71)
-2.9 (1.67)
1.3 (1.66)
-0.6 (1.67)
4.1 (1.63)
Column vs Placebo
Difference
95% C.I.
p-value
2.9
(-1.9, 7.6)
0.239
-2.0
(-6.7, 2.6)
0.394
2.2
(-2.5, 6.9)
0.356
0.3
(-4.4, 5.0)
0.904
5.0
(0.4, 9.7)
0.035
CONFIDENTIAL
731
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
96
95
96
99
LS Mean Change (SE) 0.3 (1.68)
2.7 (1.69)
-2.4 (1.65)
1.5 (1.66)
-0.6 (1.65)
2.3 (1.63)
Column vs Placebo
Difference
95% C.I.
p-value
2.3
(-2.4, 7.0)
0.329
-2.7
(-7.3, 1.9)
0.250
1.2
(-3.4, 5.9)
0.604
-0.9
(-5.6, 3.7)
0.687
2.0
(-2.7, 6.6)
0.403
CONFIDENTIAL
732
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
95
96
99
LS Mean Change (SE) 3.7 (1.77)
5.0 (1.77)
0.1 (1.73)
2.8 (1.74)
-0.3 (1.74)
0.6 (1.71)
Column vs Placebo
Difference
95% C.I.
p-value
1.2
(-3.7, 6.2)
0.620
-3.6
(-8.4, 1.3)
0.147
-0.9
(-5.8, 4.0)
0.720
-4.0
(-8.9, 0.8)
0.103
-3.1
(-8.0, 1.7)
0.205
CONFIDENTIAL
733
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 2.1 (1.73)
2.7 (1.73)
-0.6 (1.69)
1.3 (1.72)
-0.5 (1.71)
3.5 (1.68)
Column vs Placebo
Difference
95% C.I.
p-value
0.7
(-4.2, 5.5)
0.790
-2.7
(-7.4, 2.1)
0.270
-0.7
(-5.5, 4.1)
0.767
-2.5
(-7.3, 2.2)
0.300
1.4
(-3.4, 6.2)
0.565
CONFIDENTIAL
734
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
85
93
91
92
96
LS Mean Change (SE) 0.1 (1.70)
-0.3 (1.75)
-0.3 (1.67)
0.5 (1.69)
-0.2 (1.68)
2.4 (1.65)
Column vs Placebo
Difference
95% C.I.
p-value
-0.4
(-5.2, 4.4)
0.877
-0.3
(-5.0, 4.3)
0.885
0.4
(-4.3, 5.1)
0.870
-0.3
(-5.0, 4.4)
0.907
2.3
(-2.4, 7.0)
0.338
CONFIDENTIAL
735
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -1.9 (1.67)
1.6 (1.71)
-2.0 (1.63)
-1.1 (1.65)
1.2 (1.63)
-1.2 (1.60)
Column vs Placebo
Difference
95% C.I.
p-value
3.5
(-1.2, 8.2)
0.149
-0.2
(-4.8, 4.4)
0.944
0.8
(-3.8, 5.4)
0.737
3.0
(-1.5, 7.6)
0.192
0.7
(-3.9, 5.2)
0.777
CONFIDENTIAL
736
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) 0.2 (1.80)
1.0 (1.84)
-2.4 (1.76)
1.1 (1.77)
0.7 (1.76)
-1.5 (1.72)
Column vs Placebo
Difference
95% C.I.
p-value
0.9
(-4.2, 6.0)
0.731
-2.6
(-7.5, 2.4)
0.307
1.0
(-4.0, 5.9)
0.707
0.5
(-4.4, 5.5)
0.828
-1.6
(-6.5, 3.3)
0.520
CONFIDENTIAL
737
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
88
86
92
91
93
97
LS Mean Change (SE) 2.5 (1.73)
1.0 (1.75)
-3.4 (1.68)
0.6 (1.69)
-0.7 (1.67)
1.5 (1.64)
Column vs Placebo
Difference
95% C.I.
p-value
-1.5
(-6.4, 3.4)
0.544
-5.9
(-10.7, -1.2)
0.014
-1.9
(-6.7, 2.9)
0.431
-3.2
(-7.9, 1.5)
0.185
-1.0
(-5.7, 3.7)
0.677
CONFIDENTIAL
738
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
85
83
90
88
93
95
LS Mean Change (SE) -0.4 (1.81)
-0.6 (1.83)
-0.6 (1.75)
-0.1 (1.77)
2.1 (1.73)
4.1 (1.71)
Column vs Placebo
Difference
95% C.I.
p-value
-0.3
(-5.3, 4.8)
0.922
-0.2
(-5.1, 4.8)
0.943
0.2
(-4.8, 5.2)
0.925
2.5
(-2.4, 7.4)
0.320
4.5
(-0.4, 9.4)
0.072
CONFIDENTIAL
739
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
98
LS Mean Change (SE) 0.1 (1.69)
-2.3 (1.72)
-0.2 (1.65)
0.5 (1.67)
-0.7 (1.63)
3.2 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value
-2.4
(-7.1, 2.4)
0.331
-0.3
(-5.0, 4.3)
0.889
0.4
(-4.3, 5.0)
0.881
-0.8
(-5.4, 3.8)
0.742
3.1
(-1.5, 7.7)
0.186
CONFIDENTIAL
740
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) 1.9 (1.83)
0.9 (1.86)
-1.0 (1.79)
1.7 (1.81)
0.2 (1.77)
2.6 (1.73)
Column vs Placebo
Difference
95% C.I.
p-value
-0.9
(-6.1, 4.2)
0.720
-2.9
(-7.9, 2.1)
0.259
-0.2
(-5.3, 4.9)
0.935
-1.6
(-6.6, 3.4)
0.522
0.7
(-4.2, 5.7)
0.768
CONFIDENTIAL
741
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 16
Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 4.5 (1.88)
1.6 (1.90)
1.8 (1.83)
2.5 (1.85)
3.3 (1.80)
2.6 (1.76)
Column vs Placebo
Difference
95% C.I.
p-value
-3.0
(-8.2, 2.3)
0.268
-2.7
(-7.9, 2.4)
0.295
-2.1
(-7.2, 3.1)
0.438
-1.3
(-6.4, 3.9)
0.630
-1.9
(-7.0, 3.2)
0.455
CONFIDENTIAL
742
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
97
100
99
98
102
LS Mean Change (SE) -5.1 (1.69) -2.8 (1.74)
-0.3 (1.70)
-0.8 (1.71)
1.0 (1.72)
4.2 (1.69)
Column vs Placebo
Difference
95% C.I.
p-value
2.3
(-2.5, 7.1)
0.350
4.9
(0.1, 9.6)
0.043
4.3
(-0.4, 9.0)
0.075
6.1
(1.3, 10.8)
0.012
9.3
(4.6, 14.1)
<0.001
CONFIDENTIAL
743
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
100
98
100
100
LS Mean Change (SE) -7.2 (1.73) -4.3 (1.73)
-3.1 (1.73)
-4.8 (1.75)
-5.2 (1.73)
-0.5 (1.74)
Column vs Placebo
Difference
95% C.I.
p-value
2.8
(-2.0, 7.7)
0.250
4.1
(-0.8, 8.9)
0.099
2.4
(-2.5, 7.2)
0.337
2.0
(-2.8, 6.8)
0.411
6.6
(1.8, 11.5)
0.007
CONFIDENTIAL
744
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
98
100
101
LS Mean Change (SE) -3.7 (1.66) -4.8 (1.66)
-5.3 (1.65)
-4.0 (1.68)
-4.8 (1.66)
0.9 (1.66)
Column vs Placebo
Difference
95% C.I.
p-value
-1.1
(-5.7, 3.6)
0.646
-1.6
(-6.2, 3.0)
0.494
-0.3
(-4.9, 4.4)
0.908
-1.1
(-5.7, 3.5)
0.643
4.6
(0.0, 9.3)
0.050
CONFIDENTIAL
745
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
0.8 (1.79) -3.5 (1.79)
-0.7 (1.78)
1.2 (1.80)
-3.8 (1.78)
-0.4 (1.80)
Column vs Placebo
Difference
95% C.I.
p-value
-4.3
(-9.3, 0.7)
0.091
-1.6
(-6.5, 3.4)
0.536
0.4
(-4.6, 5.4)
0.880
-4.7
(-9.6, 0.3)
0.065
-1.2
(-6.2, 3.8)
0.632
CONFIDENTIAL
746
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
91
95
96
95
100
LS Mean Change (SE) -2.4 (1.97)
1.0 (1.98)
-2.0 (1.93)
2.1 (1.92)
1.8 (1.93)
10.1 (1.88)
Column vs Placebo
Difference
95% C.I.
p-value
3.5
(-2.0, 9.0)
0.215
0.5
(-4.9, 5.9)
0.860
4.6
(-0.8, 10.0)
0.096
4.2
(-1.2, 9.6)
0.125
12.5
(7.1, 17.9)
<0.001
CONFIDENTIAL
747
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
96
95
96
99
LS Mean Change (SE) -1.9 (2.03)
0.4 (2.03)
-4.3 (1.99)
-0.7 (2.00)
-2.0 (1.99)
3.6 (1.96)
Column vs Placebo
Difference
95% C.I.
p-value
2.3
(-3.3, 8.0)
0.418
-2.4
(-8.0, 3.2)
0.395
1.2
(-4.4, 6.8)
0.664
-0.1
(-5.7, 5.4)
0.965
5.5
(0.0, 11.1)
0.051
CONFIDENTIAL
748
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 7 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
95
96
99
LS Mean Change (SE) 3.0 (2.09)
2.7 (2.09)
-0.8 (2.04)
1.0 (2.06)
-1.5 (2.05)
0.7 (2.02)
Column vs Placebo
Difference
95% C.I.
p-value
-0.3
(-6.1, 5.5)
0.918
-3.8
(-9.5, 2.0)
0.196
-2.0
(-7.8, 3.8)
0.500
-4.4
(-10.2, 1.3)
0.128
-2.2
(-8.0, 3.5)
0.443
CONFIDENTIAL
749
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 8 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 2.3 (2.01)
1.6 (2.01)
-2.1 (1.96)
-0.2 (1.99)
0.0 (1.98)
4.8 (1.95)
Column vs Placebo
Difference
95% C.I.
p-value
-0.7
(-6.3, 4.9)
0.804
-4.4
(-9.9, 1.1)
0.120
-2.5
(-8.0, 3.1)
0.385
-2.3
(-7.8, 3.2)
0.416
2.5
(-3.0, 8.0)
0.379
CONFIDENTIAL
750
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 9 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
85
93
91
92
96
LS Mean Change (SE) -1.4 (1.98)
-0.4 (2.04)
1.3 (1.95)
1.6 (1.96)
3.7 (1.96)
9.3 (1.92)
Column vs Placebo
Difference
95% C.I.
p-value
1.0
(-4.6, 6.6)
0.724
2.7
(-2.8, 8.2)
0.331
3.1
(-2.4, 8.6)
0.270
5.1
(-0.4, 10.6)
0.067
10.8
(5.3, 16.2)
<0.001
CONFIDENTIAL
751
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 10 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -5.8 (1.98)
-1.0 (2.02)
-3.6 (1.94)
-2.2 (1.96)
2.4 (1.94)
1.5 (1.90)
Column vs Placebo
Difference
95% C.I.
p-value
4.8
(-0.8, 10.4)
0.093
2.2
(-3.2, 7.7)
0.426
3.6
(-1.9, 9.1)
0.199
8.2
(2.7, 13.6)
0.003
7.3
(1.9, 12.8)
0.008
CONFIDENTIAL
752
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 11 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -0.6 (2.12)
-0.2 (2.17)
-4.0 (2.08)
0.9 (2.10)
2.6 (2.08)
0.9 (2.04)
Column vs Placebo
Difference
95% C.I.
p-value
0.4
(-5.6, 6.4)
0.903
-3.3
(-9.2, 2.5)
0.260
1.5
(-4.4, 7.4)
0.617
3.2
(-2.6, 9.0)
0.280
1.5
(-4.3, 7.4)
0.605
CONFIDENTIAL
753
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 12 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
88
86
92
91
93
97
LS Mean Change (SE) 2.9 (2.04)
-0.3 (2.06)
-4.2 (1.98)
-0.8 (1.99)
-0.2 (1.97)
2.4 (1.93)
Column vs Placebo
Difference
95% C.I.
p-value
-3.2
(-9.0, 2.5)
0.268
-7.1
(-12.7, -1.5)
0.013
-3.8
(-9.4, 1.9)
0.190
-3.1
(-8.7, 2.4)
0.272
-0.6
(-6.1, 5.0)
0.843
CONFIDENTIAL
754
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 13 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
85
83
90
88
93
95
LS Mean Change (SE) -0.6 (2.03)
-1.6 (2.05)
-1.3 (1.96)
0.2 (1.98)
4.3 (1.93)
10.2 (1.91)
Column vs Placebo
Difference
95% C.I.
p-value
-1.0
(-6.7, 4.7)
0.720
-0.7
(-6.2, 4.9)
0.809
0.8
(-4.7, 6.4)
0.768
4.9
(-0.6, 10.4)
0.081
10.8
(5.3, 16.3)
<0.001
CONFIDENTIAL
755
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 14 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
98
LS Mean Change (SE) -2.5 (1.90)
-5.5 (1.93)
-3.5 (1.85)
-3.2 (1.88)
-2.6 (1.83)
3.4 (1.79)
Column vs Placebo
Difference
95% C.I.
p-value
-3.0
(-8.3, 2.3)
0.270
-0.9
(-6.2, 4.3)
0.721
-0.7
(-6.0, 4.6)
0.799
0.0
(-5.2, 5.2)
0.991
6.0
(0.8, 11.1)
0.023
CONFIDENTIAL
756
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 15 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -2.7 (2.10)
-3.9 (2.14)
-5.5 (2.05)
-3.1 (2.08)
-3.1 (2.03)
1.2 (1.99)
Column vs Placebo
Difference
95% C.I.
p-value
-1.3
(-7.2, 4.7)
0.677
-2.8
(-8.6, 2.9)
0.335
-0.5
(-6.3, 5.4)
0.873
-0.4
(-6.2, 5.3)
0.886
3.9
(-1.9, 9.6)
0.186
CONFIDENTIAL
757
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 16 of 16
Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 2.1 (2.21)
-2.2 (2.23)
-3.3 (2.15)
-1.5 (2.17)
0.4 (2.12)
1.2 (2.07)
Column vs Placebo
Difference
95% C.I.
p-value
-4.3
(-10.5, 1.9)
0.172
-5.4
(-11.5, 0.6)
0.080
-3.7
(-9.8, 2.5)
0.241
-1.7
(-7.7, 4.3)
0.571
-0.9
(-6.9, 5.0)
0.757
CONFIDENTIAL
758
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
9.8 (1.28) 11.0 (1.28)
11.8 (1.28)
11.3 (1.28)
9.9 (1.28)
12.1 (1.28)
Column vs Placebo
Difference
95% C.I.
p-value
1.2
(-2.4, 4.7)
0.520
2.0
(-1.6, 5.5)
0.275
1.5
(-2.1, 5.0)
0.416
0.0
(-3.5, 3.6)
0.987
2.2
(-1.3, 5.8)
0.219
CONFIDENTIAL
759
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 11.0 (1.57)
13.3 (1.57)
7.5 (1.53)
11.6 (1.54)
9.2 (1.54)
12.3 (1.51)
Column vs Placebo
Difference
95% C.I.
p-value
2.3
(-2.1, 6.7)
0.299
-3.5
(-7.8, 0.8)
0.113
0.6
(-3.7, 5.0)
0.775
-1.7
(-6.0, 2.6)
0.432
1.3
(-3.0, 5.7)
0.538
CONFIDENTIAL
760
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
86
93
91
94
97
LS Mean Change (SE) 10.3 (1.51)
10.6 (1.55)
7.7 (1.48)
10.1 (1.50)
10.5 (1.47)
10.5 (1.45)
Column vs Placebo
Difference
95% C.I.
p-value
0.2
(-4.0, 4.5)
0.909
-2.6
(-6.8, 1.5)
0.211
-0.3
(-4.4, 3.9)
0.904
0.1
(-4.0, 4.3)
0.952
0.2
(-3.9, 4.3)
0.926
CONFIDENTIAL
761
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 11.7 (1.58)
8.9 (1.60)
10.2 (1.55)
10.6 (1.57)
11.7 (1.53)
14.1 (1.49)
Column vs Placebo
Difference
95% C.I.
p-value
-2.8
(-7.3, 1.6)
0.211
-1.5
(-5.9, 2.8)
0.493
-1.1
(-5.5, 3.3)
0.611
-0.1
(-4.4, 4.2)
0.969
2.4
(-1.9, 6.7)
0.278
CONFIDENTIAL
762
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
9.1 (1.59) 10.3 (1.60)
10.5 (1.60)
10.1 (1.60)
10.0 (1.59)
13.5 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value
1.2
(-3.3, 5.6)
0.608
1.4
(-3.1, 5.8)
0.541
1.0
(-3.5, 5.4)
0.664
0.9
(-3.5, 5.3)
0.693
4.4
(-0.1, 8.8)
0.055
CONFIDENTIAL
763
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 12.8 (1.86)
15.0 (1.86)
8.8 (1.82)
12.8 (1.83)
13.0 (1.83)
18.0 (1.79)
Column vs Placebo
Difference
95% C.I.
p-value
2.2
(-3.0, 7.4)
0.417
-4.0
(-9.1, 1.1)
0.126
0.0
(-5.2, 5.1)
0.986
0.2
(-4.9, 5.3)
0.943
5.2
(0.1, 10.3)
0.047
CONFIDENTIAL
764
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
86
93
91
94
97
LS Mean Change (SE) 12.3 (1.82)
11.5 (1.87)
10.4 (1.79)
13.6 (1.81)
15.7 (1.78)
17.7 (1.75)
Column vs Placebo
Difference
95% C.I.
p-value
-0.7
(-5.9, 4.4)
0.778
-1.8
(-6.8, 3.2)
0.475
1.3
(-3.7, 6.4)
0.601
3.4
(-1.6, 8.4)
0.177
5.4
(0.5, 10.4)
0.033
CONFIDENTIAL
765
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 12.3 (1.86)
8.0 (1.88)
9.0 (1.81)
10.0 (1.84)
13.4 (1.79)
18.5 (1.75)
Column vs Placebo
Difference
95% C.I.
p-value
-4.2
(-9.5, 1.0)
0.111
-3.2
(-8.3, 1.9)
0.213
-2.3
(-7.5, 2.9)
0.381
1.1
(-3.9, 6.2)
0.659
6.3
(1.2, 11.3)
0.015
CONFIDENTIAL
766
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
0.6 (1.12)
0.6 (1.12)
1.6 (1.12)
1.7 (1.13)
-0.4 (1.11)
2.4 (1.13)
Column vs Placebo
Difference
95% C.I.
p-value
0.0
(-3.1, 3.1)
0.996
1.0
(-2.1, 4.1)
0.542
1.1
(-2.0, 4.3)
0.477
-1.0
(-4.1, 2.1)
0.530
1.7
(-1.4, 4.9)
0.278
CONFIDENTIAL
767
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 1.8 (1.47)
3.5 (1.47)
-1.0 (1.43)
1.9 (1.46)
-0.8 (1.45)
2.2 (1.43)
Column vs Placebo
Difference
95% C.I.
p-value
1.6
(-2.5, 5.7)
0.436
-2.9
(-6.9, 1.2)
0.165
0.0
(-4.1, 4.1)
0.994
-2.6
(-6.7, 1.4)
0.205
0.3
(-3.7, 4.4)
0.870
CONFIDENTIAL
768
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
86
92
91
93
96
LS Mean Change (SE) 0.4 (1.47)
1.0 (1.48)
-2.4 (1.42)
0.3 (1.43)
0.3 (1.42)
-0.4 (1.40)
Column vs Placebo
Difference
95% C.I.
p-value
0.6
(-3.5, 4.7)
0.780
-2.8
(-6.8, 1.2)
0.174
0.0
(-4.1, 4.0)
0.988
0.0
(-4.1, 4.0)
0.981
-0.8
(-4.8, 3.2)
0.687
CONFIDENTIAL
769
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 1.8 (1.55)
0.1 (1.56)
-0.1 (1.51)
1.3 (1.52)
1.0 (1.48)
2.7 (1.45)
Column vs Placebo
Difference
95% C.I.
p-value
-1.7
(-6.0, 2.7)
0.452
-1.9
(-6.2, 2.3)
0.371
-0.5
(-4.8, 3.8)
0.825
-0.8
(-5.0, 3.4)
0.702
0.9
(-3.3, 5.1)
0.660
CONFIDENTIAL
770
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 4
Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE) -3.4 (1.33) -4.0 (1.33)
-2.9 (1.33)
-2.3 (1.34)
-3.8 (1.32)
0.6 (1.34)
Column vs Placebo
Difference
95% C.I.
p-value
-0.5
(-4.3, 3.2)
0.776
0.5
(-3.1, 4.2)
0.770
1.1
(-2.6, 4.8)
0.561
-0.3
(-4.0, 3.3)
0.852
4.0
(0.3, 7.8)
0.034
CONFIDENTIAL
771
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 4
Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 0.9 (1.68)
1.7 (1.69)
-2.0 (1.64)
0.4 (1.67)
-1.0 (1.66)
3.8 (1.64)
Column vs Placebo
Difference
95% C.I.
p-value
0.8
(-3.9, 5.5)
0.731
-2.9
(-7.5, 1.7)
0.215
-0.5
(-5.2, 4.2)
0.831
-1.9
(-6.5, 2.8)
0.429
2.9
(-1.8, 7.5)
0.225
CONFIDENTIAL
772
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 4
Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
86
92
91
93
96
LS Mean Change (SE) -0.9 (1.67)
-0.5 (1.68)
-3.3 (1.62)
-0.2 (1.62)
1.9 (1.61)
2.0 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value
0.4
(-4.3, 5.1)
0.860
-2.4
(-7.0, 2.2)
0.306
0.6
(-3.9, 5.2)
0.782
2.8
(-1.8, 7.3)
0.230
2.9
(-1.7, 7.4)
0.218
CONFIDENTIAL
773
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 4
Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) -1.2 (1.71)
-3.5 (1.73)
-4.0 (1.67)
-2.3 (1.68)
-1.2 (1.64)
2.6 (1.61)
Column vs Placebo
Difference
95% C.I.
p-value
-2.3
(-7.1, 2.5)
0.343
-2.8
(-7.5, 1.8)
0.234
-1.2
(-5.9, 3.6)
0.632
0.0
(-4.7, 4.7)
>0.999
3.8
(-0.9, 8.4)
0.109
CONFIDENTIAL
774
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
84
86
87
86
86
5.20
5.16
5.02
5.13
5.16
1.350
1.187
1.019
1.078
0.944
4.90
5.00
4.90
4.90
5.00
3.8
3.9
4.1
4.2
4.3
14.0
13.9
13.4
13.2
12.0
3mcg
101
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
100
98
101
101
99
5.23
5.21
5.19
5.19
5.25
1.462
1.384
1.359
1.280
1.049
5.00
5.00
5.00
5.00
5.00
3.7
4.0
4.0
3.8
3.8
17.2
17.0
17.0
16.2
12.7
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
84
82
84
81
83
5.21
5.13
5.08
5.20
5.17
1.474
1.100
0.824
0.963
0.873
4.90
4.90
4.90
5.00
5.00
3.9
3.9
2.5
4.0
3.7
15.1
12.0
9.4
9.1
9.2
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
775
Day 28
CONFIDENTIAL
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
Placebo
102 Day 1
Pre-dose
100 5.07 1.039 5.00
1.7
13.4
(plasma efficacy)
(MMOL/L)
10 mins
102 5.15 1.161 5.00
3.9
12.7
1 hour
101 5.13 1.135 4.90
4.1
12.8
2 hours
100 5.19 1.152 4.95
3.9
12.8
4 hours
100 5.24 1.092 4.90
4.0
12.7
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
91
89
89
91
88
5.03
5.00
4.95
5.04
5.09
0.674
0.654
0.615
0.871
0.763
4.90
4.90
4.90
4.90
4.95
3.3
3.7
3.9
3.6
3.8
8.1
8.1
8.2
9.3
7.7
12.5mcg
100
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
98
98
98
97
5.19
5.16
5.18
5.20
5.25
1.399
1.380
1.225
1.240
1.344
5.00
4.95
5.00
4.90
5.10
3.8
3.8
2.8
3.8
1.8
14.8
14.4
14.0
13.8
14.4
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
89
87
86
88
87
5.20
5.07
5.32
5.33
5.35
0.975
0.974
1.341
1.321
1.329
5.00
4.90
5.00
5.05
5.00
3.5
0.6
1.7
2.3
3.9
11.5
10.4
13.8
13.3
13.9
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
776
Day 28
CONFIDENTIAL
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
6.25mcg
101 Day 1
Pre-dose
100 4.98 0.743 4.90
3.8
8.8
(plasma efficacy)
(MMOL/L)
10 mins
99 4.91 0.700 4.80
3.7
8.6
1 hour
101 4.93 0.763 4.80
3.6
9.5
2 hours
100 4.94 0.826 4.80
3.8
9.5
4 hours
101 5.02 0.731 4.90
3.8
9.5
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
92
92
92
93
92
5.17
5.19
5.16
5.17
5.38
1.194
1.051
0.863
0.684
1.065
5.00
5.10
5.00
5.10
5.10
3.8
3.6
3.9
3.7
3.7
14.3
13.2
11.5
9.4
10.1
50mcg
102
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
99
99
98
97
98
5.24
5.31
5.41
5.43
5.46
1.835
1.710
1.860
1.725
1.528
5.00
5.10
5.10
5.10
5.15
0.6
3.9
4.1
4.0
3.8
20.1
20.2
20.6
18.5
16.5
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
94
96
95
94
5.28
5.35
5.41
5.33
5.27
1.770
1.774
1.667
1.575
1.333
4.90
4.95
5.10
5.00
4.95
3.3
3.5
3.5
3.5
2.5
17.4
17.7
17.0
15.3
14.9
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
777
Day 28
CONFIDENTIAL
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
25mcg
101 Day 1
Pre-dose
101 5.11 0.766 5.10
3.4
9.8
(plasma efficacy)
(MMOL/L)
10 mins
100 5.16 0.885 5.10
3.9
9.5
1 hour
99 5.15 0.910 5.00
3.4
10.4
2 hours
100 5.13 0.827 5.10
3.9
9.2
4 hours
100 5.32 0.865 5.20
3.9
8.6
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
Placebo
102 Day 1
Pre-dose
89 4.33 0.417 4.30
3.7
5.5
(MMOL/L)
10 mins
93 4.36 0.681 4.20
3.4
6.9
1 hour
97 4.35 0.782 4.20
2.9
8.4
2 hours
94 4.33 0.646 4.20
3.4
7.9
4 hours
91 4.24 0.757 4.10
3.4
8.6
4.36
4.31
4.39
4.41
4.35
0.499
0.496
0.507
0.723
0.647
4.20
4.20
4.30
4.20
4.25
3.7
3.5
3.6
3.5
3.3
6.4
6.6
6.2
7.8
7.8
3mcg
101
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
97
92
97
94
95
4.23
4.32
4.24
4.25
4.17
0.420
0.708
0.480
0.564
0.582
4.20
4.20
4.10
4.10
4.10
3.3
3.2
3.3
2.9
3.1
5.7
8.3
5.7
6.3
6.7
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
80
78
80
77
76
4.19
4.18
4.37
4.38
4.22
0.360
0.403
0.694
0.846
0.597
4.10
4.10
4.20
4.20
4.10
3.6
3.4
3.5
3.5
3.4
5.4
5.7
8.2
9.1
6.5
CONFIDENTIAL
86
83
84
83
80
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
778
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
6.25mcg
101 Day 1
Pre-dose
94 4.21 0.501 4.10
3.2
7.0
(MMOL/L)
10 mins
94 4.24 0.526 4.10
3.5
6.8
1 hour
98 4.24 0.451 4.10
3.6
5.7
2 hours
95 4.26 0.560 4.10
3.1
6.6
4 hours
96 4.34 0.802 4.10
3.3
9.1
4.21
4.24
4.33
4.24
4.20
0.587
0.469
0.567
0.505
0.599
4.20
4.20
4.20
4.20
4.10
3.5
3.3
3.4
3.1
3.3
8.2
5.9
6.1
6.0
7.7
12.5mcg
100
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
91
95
93
88
4.27
4.24
4.34
4.28
4.31
0.568
0.578
0.712
0.613
0.884
4.20
4.10
4.20
4.20
4.15
3.4
3.1
3.1
3.5
1.0
6.8
6.6
7.7
6.5
8.3
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
87
85
86
86
83
4.16
4.28
4.28
4.24
4.16
0.389
0.639
0.651
0.551
0.557
4.10
4.20
4.20
4.15
4.00
3.5
3.3
3.4
3.4
3.3
5.7
7.9
8.5
6.7
6.4
CONFIDENTIAL
86
89
87
83
84
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
779
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 6
Table 8.54
Summary of Fasting Potassium and Glucose
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
25mcg
101 Day 1
Pre-dose
94 4.24 0.486 4.20
2.9
6.4
(MMOL/L)
10 mins
94 4.35 0.734 4.20
2.7
8.3
1 hour
88 4.35 0.755 4.20
2.6
7.3
2 hours
92 4.33 0.665 4.20
2.9
6.5
4 hours
93 4.32 0.721 4.20
3.0
6.8
4.33
4.29
4.42
4.36
4.37
0.466
0.653
0.734
0.610
0.739
4.20
4.10
4.20
4.20
4.10
3.4
2.9
3.4
3.3
3.0
6.1
8.2
7.3
6.7
7.4
50mcg
102
Day 1
Pre-dose
10 mins
1 hour
2 hours
4 hours
95
91
94
92
94
4.42
4.28
4.32
4.24
4.31
0.877
0.654
0.828
0.701
0.826
4.20
4.10
4.10
4.10
4.10
3.3
3.2
3.2
3.1
3.2
9.1
7.0
8.8
7.1
7.6
Day 28
Pre-dose
10 mins
1 hour
2 hours
4 hours
94
89
92
94
92
4.34
4.30
4.34
4.28
4.28
0.728
0.651
0.625
0.630
0.723
4.20
4.10
4.20
4.10
4.10
3.5
3.4
3.5
3.3
3.3
8.3
7.6
6.8
8.1
7.4
CONFIDENTIAL
89
89
89
92
87
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
780
Day 28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 3
Table 8.55
Summary of Non-Fasting Potassium
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
Placebo
102 Day 7
Pre-dose
90 4.24 0.358 4.20
3.5
5.4
(MMOL/L)
10 mins
90 4.18 0.401 4.10
3.5
5.4
1 hour
87 4.19 0.509 4.10
3.4
6.3
2 hours
90 4.10 0.463 4.00
3.1
5.7
4 hours
88 4.04 0.380 4.00
3.3
5.2
4.26
4.27
4.26
4.14
4.17
0.480
0.650
0.674
0.513
0.563
4.20
4.10
4.10
4.00
4.10
3.3
3.2
3.4
3.4
3.4
6.4
7.1
8.6
7.3
7.2
3mcg
101
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
91
92
92
93
4.22
4.11
4.13
4.11
4.03
0.404
0.330
0.323
0.421
0.384
4.20
4.10
4.10
4.10
4.00
3.5
3.4
3.5
3.3
3.1
5.7
4.9
5.0
5.7
5.0
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
84
83
85
84
81
4.15
4.07
4.13
4.10
4.02
0.322
0.304
0.427
0.361
0.358
4.10
4.00
4.00
4.00
4.00
3.5
3.5
3.3
3.4
3.4
5.0
4.9
5.8
5.7
5.1
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
87
86
83
84
86
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
781
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 3
Table 8.55
Summary of Non-Fasting Potassium
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
6.25mcg
101 Day 7
Pre-dose
95 4.22 0.428 4.10
3.2
5.6
(MMOL/L)
10 mins
92 4.10 0.409 4.10
3.4
5.3
1 hour
91 4.11 0.449 4.10
3.2
5.7
2 hours
94 4.08 0.399 4.10
3.2
5.4
4 hours
94 4.04 0.394 4.00
3.2
5.5
4.13
4.11
4.11
4.09
4.01
0.332
0.385
0.382
0.432
0.369
4.10
4.10
4.10
4.00
4.00
3.2
3.1
3.3
3.2
3.2
5.3
5.3
5.4
5.7
5.3
12.5mcg
100
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
94
91
92
88
4.21
4.16
4.16
4.06
4.01
0.415
0.470
0.461
0.424
0.489
4.20
4.10
4.10
4.00
4.00
3.2
3.0
3.0
3.1
3.2
6.0
6.5
6.6
6.2
6.2
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
85
87
88
85
86
4.22
4.16
4.13
4.09
4.05
0.364
0.362
0.396
0.445
0.469
4.20
4.10
4.10
4.00
4.00
3.6
3.6
3.3
2.6
3.4
5.8
6.1
6.1
6.1
6.6
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
92
90
89
91
93
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
782
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 3
Table 8.55
Summary of Non-Fasting Potassium
Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
25mcg
101 Day 7
Pre-dose
90 4.27 0.448 4.20
3.3
5.5
(MMOL/L)
10 mins
91 4.20 0.451 4.10
3.3
5.7
1 hour
89 4.18 0.480 4.10
3.2
6.5
2 hours
91 4.11 0.491 4.00
3.1
6.2
4 hours
91 4.11 0.693 4.00
3.1
8.6
4.25
4.17
4.12
4.11
4.10
0.450
0.382
0.429
0.492
0.518
4.20
4.10
4.00
4.00
4.05
3.2
3.2
3.2
3.2
3.2
6.7
5.8
5.8
6.3
6.2
50mcg
102
Day 7
Pre-dose
10 mins
1 hour
2 hours
4 hours
92
94
94
91
93
4.31
4.18
4.16
4.13
4.09
0.567
0.681
0.701
0.753
0.753
4.20
4.10
4.10
4.00
3.90
2.9
3.1
2.2
2.7
2.9
7.2
9.1
9.1
9.1
9.1
Day 14
Pre-dose
10 mins
1 hour
2 hours
4 hours
93
94
94
93
92
4.18
4.18
4.10
4.10
4.02
0.459
0.557
0.442
0.531
0.508
4.10
4.10
4.00
4.10
4.00
3.1
2.9
3.3
3.3
3.0
6.7
7.3
5.9
7.2
6.8
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
92
88
90
86
88
YM2008/00019/00
B2C109575
Pre-dose
10 mins
1 hour
2 hours
4 hours
783
Day 14
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
784
2 hours
101
0
94
(93%)
101
0
90
5
2
n
To Low
To Normal or No
Change
To High
Missing
(89%)
101
1
95
(<1%)
(94%)
98
2
90
(5%)
(2%)
10
1
(10%)
(<1%)
4
1
(4%)
(<1%)
6
0
100
0
89
(89%)
101
1
90
(<1%)
(89%)
100
2
93
(2%)
(93%)
98
0
89
(91%)
100
0
88
9
2
(9%)
(2%)
9
1
(9%)
(<1%)
4
1
(4%)
(1%)
8
1
(8%)
(1%)
12
0
(2%)
(92%)
(6%)
99
1
90
8
0
(1%)
(91%)
(8%)
(88%)
(12%)
98
0
89
(91%)
8
1
(8%)
(1%)
97
0
86
(89%)
10
1
(10%)
(1%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
CONFIDENTIAL
1 hour
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
10 mins
(1%)
(85%)
84
0
75
(89%)
91
2
75
(2%)
(82%)
89
1
73
(1%)
(82%)
92
1
83
10
2
(12%)
(2%)
8
1
(10%)
(1%)
13
1
(14%)
(1%)
14
1
(16%)
(1%)
8
0
86
0
77
(90%)
82
0
73
(89%)
89
1
76
(1%)
(85%)
87
1
76
(1%)
(87%)
92
1
81
7
2
(8%)
(2%)
8
1
(10%)
(1%)
11
1
(12%)
(1%)
9
1
(10%)
(1%)
10
0
(1%)
(90%)
(9%)
(1%)
(88%)
(11%)
95
4
78
(4%)
(82%)
11
2
(12%)
(2%)
94
2
83
(2%)
(88%)
8
1
(9%)
(1%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
84
1
71
CONFIDENTIAL
785
Day 28 Pre-dose n
To Low
To Normal or No
Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
786
4 hours
86
0
76
(88%)
81
0
71
8
2
n
To Low
To Normal or No
Change
To High
Missing
(88%)
91
1
81
(1%)
(89%)
88
1
69
(1%)
(78%)
93
1
78
(9%)
(2%)
9
1
(11%)
(1%)
8
1
(9%)
(1%)
17
1
(19%)
(1%)
14
0
86
0
78
(91%)
83
1
73
(1%)
(88%)
88
1
76
(1%)
(86%)
87
0
69
(79%)
92
1
75
6
2
(7%)
(2%)
8
1
(10%)
(1%)
10
1
(11%)
(1%)
17
1
(20%)
(1%)
16
0
(1%)
(84%)
(15%)
(1%)
(82%)
(17%)
95
1
80
(1%)
(84%)
12
2
(13%)
(2%)
94
1
80
(1%)
(85%)
12
1
(13%)
(1%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
CONFIDENTIAL
2 hours
Protocol: B2C109575
Population: Intent-to-Treat
Page 4 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
787
2 hours
97
1
81
(1%)
(84%)
97
0
90
(93%)
98
0
89
5
10
(5%)
(10%)
3
4
n
To Low
To Normal or No
Change
To High
Missing
94
0
81
2
11
(91%)
95
0
88
(3%)
(4%)
(86%)
94
0
88
(2%)
(12%)
4
2
(93%)
88
0
77
3
6
(3%)
(6%)
4
3
(94%)
95
1
86
(1%)
(91%)
(4%)
(2%)
3
5
(3%)
(5%)
(88%)
94
2
84
(2%)
(89%)
(4%)
(3%)
6
5
(7%)
(6%)
3
5
(3%)
(5%)
93
0
86
(92%)
92
2
80
(2%)
(87%)
92
3
80
(3%)
(87%)
3
4
(3%)
(4%)
5
5
(5%)
(5%)
5
4
(5%)
(4%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
CONFIDENTIAL
1 hour
Protocol: B2C109575
Population: Intent-to-Treat
Page 5 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
10 mins
(84%)
80
0
75
3
11
(94%)
86
0
79
(3%)
(13%)
83
0
70
3
10
(92%)
87
0
81
1
4
(1%)
(5%)
(84%)
78
3
70
(4%)
(12%)
1
4
(93%)
89
0
80
1
6
(1%)
(7%)
(4%)
(90%)
89
1
80
(1%)
(5%)
2
6
(90%)
94
0
86
(91%)
1
5
(1%)
(6%)
2
7
(2%)
(8%)
2
6
(2%)
(6%)
(1%)
(90%)
85
1
76
(1%)
(89%)
89
0
79
(89%)
89
1
79
(1%)
(89%)
(2%)
(7%)
4
4
(5%)
(5%)
3
7
(3%)
(8%)
4
5
(4%)
(6%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
86
0
72
CONFIDENTIAL
788
Day 28 Pre-dose n
To Low
To Normal or No
Change
To High
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 6 of 6
Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range
789
4 hours
83
0
67
(81%)
77
0
68
n
To Low
To Normal or No
Change
To High
Missing
(88%)
83
2
73
(2%)
(88%)
86
1
79
(1%)
(92%)
92
0
79
6
10
(7%)
(12%)
80
1
66
4
9
(86%)
94
3
84
(3%)
(89%)
5
4
(6%)
(5%)
3
5
(4%)
(6%)
2
4
(2%)
(5%)
6
7
(7%)
(8%)
2
5
(2%)
(5%)
(1%)
(83%)
76
1
68
(1%)
(89%)
84
3
73
(4%)
(87%)
83
1
76
(1%)
(92%)
87
0
76
(87%)
92
4
78
(4%)
(85%)
(5%)
(11%)
3
4
(4%)
(5%)
3
5
(4%)
(6%)
2
4
(2%)
(5%)
5
6
(6%)
(7%)
5
5
(5%)
(5%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
Note:
Note:
n
To Low
To Normal or No
Change
To High
Missing
CONFIDENTIAL
2 hours
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 3
Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range
790
1 hour
2 hours
90
0
78
2
10
(87%)
(2%)
(11%)
91
1
86
0
4
n
To Low
To Normal or No Change
To High
Missing
87
1
75
1
10
(1%)
(86%)
(1%)
(11%)
92
0
88
0
4
n
To Low
To Normal or No Change
To High
Missing
90
3
77
0
10
(3%)
(86%)
(11%)
92
3
84
1
4
(8%)
94
1
88
0
5
(4%)
91
4
79
2
6
(4%)
(87%)
(2%)
(7%)
91
1
85
1
4
(3%)
(91%)
(1%)
(4%)
94
5
82
1
6
(5%)
(87%)
(1%)
(6%)
92
1
87
0
4
(1%)
(95%)
(4%)
(96%)
92
2
83
0
7
(2%)
(90%)
(5%)
91
0
82
3
6
(1%)
(93%)
(1%)
(4%)
89
0
81
2
6
(91%)
(2%)
(7%)
94
3
84
1
6
91
2
82
1
6
(2%)
(90%)
(1%)
(7%)
91
5
80
2
4
(1%)
(94%)
(1%)
(95%)
(4%)
(90%)
(3%)
(7%)
94
2
85
1
6
(2%)
(90%)
(1%)
(6%)
(3%)
(89%)
(1%)
(6%)
(5%)
(88%)
(2%)
(4%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
n
To Low
To Normal or No Change
To High
Missing
CONFIDENTIAL
10 mins
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 3
Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range
791
10 mins
1 hour
87
0
75
1
11
(86%)
(1%)
(13%)
84
0
80
0
4
n
To Low
To Normal or No Change
To High
Missing
86
1
72
2
11
(1%)
(84%)
(2%)
(13%)
83
0
79
0
4
n
To Low
To Normal or No Change
To High
Missing
83
1
70
2
10
(1%)
(84%)
(2%)
(12%)
85
1
79
1
4
(95%)
(5%)
92
2
84
0
6
(5%)
90
2
82
0
6
(1%)
(93%)
(1%)
(5%)
89
2
82
1
4
(95%)
(2%)
(91%)
(7%)
85
0
80
0
5
(7%)
87
0
83
0
4
(2%)
(92%)
(1%)
(4%)
88
2
81
0
5
(2%)
(91%)
(94%)
(6%)
(95%)
(5%)
(2%)
(92%)
(6%)
92
1
84
1
6
88
1
80
0
7
90
2
81
0
7
(1%)
(91%)
(1%)
(7%)
(1%)
(91%)
(8%)
(2%)
(90%)
(8%)
93
1
86
1
5
(1%)
(92%)
(1%)
(5%)
94
1
85
2
6
(1%)
(90%)
(2%)
(6%)
94
2
85
1
6
(2%)
(90%)
(1%)
(6%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
n
To Low
To Normal or No Change
To High
Missing
CONFIDENTIAL
Day 14 Pre-dose
Protocol: B2C109575
Population: Intent-to-Treat
Page 3 of 3
Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range
792
86
2
72
1
11
(2%)
(84%)
(1%)
(13%)
81
4
74
0
3
(5%)
(91%)
(4%)
93
3
84
0
6
(3%)
(90%)
(6%)
86
1
81
0
4
(1%)
(94%)
(5%)
88
3
78
1
6
(3%)
(89%)
(1%)
(7%)
92
5
80
1
6
(5%)
(87%)
(1%)
(7%)
Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
YM2008/00019/00
B2C109575
Note:
is no
whose
Note:
n
To Low
To Normal or No Change
To High
Missing
CONFIDENTIAL
4 hours
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.58
Summary of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
89
97
94
95
94
94
Mean
-0.33
-0.26
-0.23
-0.30
-0.22
-0.35
SD
0.336
0.315
0.434
0.534
0.336
0.798
Median
-0.30
-0.20
-0.10
-0.20
-0.20
-0.25
Min.
-1.3
-1.0
-1.8
-2.6
-1.5
-5.4
Max.
0.5
0.7
0.4
1.4
0.7
4.1
Day 28
77
-0.21
0.379
-0.20
-1.4
1.1
78
-0.19
0.386
-0.10
-1.5
0.8
84
-0.27
0.517
-0.20
-2.7
0.7
84
-0.26
0.518
-0.15
-2.5
0.6
90
-0.43
0.817
-0.20
-5.3
1.0
YM2008/00019/00
B2C109575
86
-0.21
0.425
-0.20
-1.5
0.7
CONFIDENTIAL
793
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.59
Summary of Maximum Decrease from Pre-Dose in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
85
80
86
86
89
94
Mean
-0.29
-0.16
-0.24
-0.18
-0.32
-0.33
SD
0.454
0.315
0.563
0.288
0.413
0.652
Median
-0.20
-0.10
-0.20
-0.10
-0.20
-0.20
Min.
-1.6
-1.3
-3.9
-1.4
-1.9
-4.3
Max.
0.7
0.6
1.3
0.7
0.5
0.9
CONFIDENTIAL
794
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.60
Summary of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
81
89
89
89
88
91
Mean
-0.44
-0.33
-0.33
-0.39
-0.33
-0.50
SD
0.428
0.410
0.549
0.508
0.450
0.741
Median
-0.40
-0.30
-0.30
-0.30
-0.30
-0.40
Min.
-1.6
-1.9
-2.8
-2.7
-1.5
-5.4
Max.
0.4
0.5
0.8
0.8
0.8
1.4
Day 14
78
-0.31
0.487
-0.30
-1.2
1.8
82
-0.36
0.398
-0.35
-1.8
0.4
87
-0.33
0.519
-0.20
-2.9
0.5
84
-0.37
0.546
-0.30
-3.0
0.7
91
-0.56
0.851
-0.40
-5.3
1.2
YM2008/00019/00
B2C109575
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
86
-0.36
0.486
-0.30
-1.9
0.7
CONFIDENTIAL
795
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.61
Summary of Maximum Decrease from Pre-Dose in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
89
91
93
92
88
91
Mean
-0.33
-0.32
-0.34
-0.33
-0.31
-0.37
SD
0.361
0.307
0.301
0.311
0.302
0.422
Median
-0.30
-0.30
-0.30
-0.20
-0.30
-0.40
Min.
-1.9
-1.5
-1.1
-1.5
-1.0
-1.4
Max.
0.3
0.4
0.3
0.5
0.4
2.4
Day 14
86
-0.26
0.349
-0.25
-1.7
0.8
84
-0.27
0.259
-0.20
-1.0
0.2
92
-0.25
0.289
-0.20
-1.4
0.5
85
-0.33
0.350
-0.20
-1.8
0.3
93
-0.32
0.297
-0.30
-1.4
0.3
YM2008/00019/00
B2C109575
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
92
-0.33
0.315
-0.25
-1.1
0.5
CONFIDENTIAL
796
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.62
Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
100
100
100
99
101
99
Mean
0.49
0.33
0.27
0.32
0.55
0.48
SD
1.092
0.679
0.686
0.738
1.036
1.117
Median
0.20
0.30
0.20
0.20
0.20
0.30
Min.
-0.9
-2.2
-0.9
-1.7
-1.5
-1.5
Max.
6.1
2.7
4.7
4.0
4.2
7.6
Day 28
85
0.38
0.908
0.30
-1.1
3.9
83
0.25
1.089
0.20
-5.2
4.0
87
0.43
1.066
0.30
-4.4
4.0
93
0.59
1.324
0.30
-4.1
5.9
94
0.55
1.562
0.40
-4.8
11.6
YM2008/00019/00
B2C109575
90
0.48
0.714
0.40
-1.0
2.9
CONFIDENTIAL
797
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.63
Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
83
84
91
88
92
94
Mean
0.29
0.27
0.38
0.45
0.55
0.47
SD
0.686
0.775
0.756
1.365
1.023
0.745
Median
0.20
0.25
0.20
0.20
0.30
0.30
Min.
-2.2
-3.1
-0.9
-1.1
-1.1
-1.0
Max.
4.1
2.8
3.6
10.0
4.9
3.5
CONFIDENTIAL
798
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.64
Summary of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
79
93
90
84
87
89
Mean
0.015
0.003
0.077
0.020
0.091
-0.140
SD
0.4182
0.3152
0.5099
0.4830
0.4102
0.6946
Median
-0.046
-0.054
0.092
-0.019
0.027
-0.075
Min.
-0.89
-0.68
-1.54
-1.46
-0.78
-5.17
Max.
2.25
1.28
1.74
1.48
1.79
1.64
Day 28
69
0.067
0.4668
0.046
-0.86
1.62
70
0.099
0.5072
0.041
-0.92
2.85
76
0.032
0.5935
0.106
-2.33
1.34
78
-0.047
0.5410
-0.020
-2.30
1.13
86
-0.050
0.6773
-0.021
-4.59
1.84
YM2008/00019/00
B2C109575
77
0.138
0.4742
0.077
-0.78
1.64
CONFIDENTIAL
799
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.65
Summary of Weighted Mean Change from Pre-Dose in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
78
74
81
82
83
91
Mean
-0.016
0.119
0.060
0.057
-0.001
-0.039
SD
0.5011
0.4849
0.5661
0.3556
0.4059
0.5720
Median
0.000
0.024
0.066
-0.012
-0.040
-0.037
Min.
-1.25
-0.87
-3.53
-0.62
-0.97
-3.86
Max.
1.68
2.35
1.65
1.23
1.34
1.12
CONFIDENTIAL
800
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.66
Summary of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
75
87
85
84
81
82
Mean
-0.218
-0.140
-0.151
-0.186
-0.109
-0.302
SD
0.4083
0.4030
0.5569
0.5207
0.4803
0.7846
Median
-0.132
-0.140
-0.100
-0.083
-0.087
-0.143
Min.
-1.26
-1.41
-2.76
-2.48
-1.33
-5.33
Max.
0.78
0.77
0.85
1.15
1.24
1.58
Day 14
72
-0.095
0.5453
-0.121
-1.10
2.12
75
-0.159
0.4103
-0.142
-1.43
0.85
86
-0.135
0.5373
-0.082
-2.73
0.76
77
-0.118
0.4553
-0.085
-2.46
0.89
85
-0.359
0.8583
-0.225
-4.70
2.13
YM2008/00019/00
B2C109575
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
82
-0.167
0.4654
-0.113
-1.48
0.81
CONFIDENTIAL
801
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.67
Summary of Weighted Mean Change from Pre-Dose in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
85
91
92
87
86
88
Mean
-0.091
-0.117
-0.138
-0.124
-0.105
-0.172
SD
0.3460
0.2987
0.2797
0.2847
0.3097
0.4119
Median
-0.102
-0.095
-0.110
-0.075
-0.109
-0.161
Min.
-1.09
-1.32
-0.91
-0.98
-0.80
-1.01
Max.
0.94
0.78
0.55
0.78
1.04
2.35
Day 14
83
-0.064
0.3847
-0.085
-1.37
1.95
78
-0.056
0.2343
-0.051
-0.63
0.51
92
-0.049
0.2666
-0.040
-0.94
0.84
81
-0.128
0.2855
-0.084
-1.12
0.42
90
-0.084
0.2912
-0.065
-1.01
0.59
YM2008/00019/00
B2C109575
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
87
-0.140
0.2822
-0.111
-1.00
0.32
CONFIDENTIAL
802
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.68
Summary of Weighted Mean Change from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
97
98
99
94
99
98
Mean
0.118
-0.018
-0.023
-0.006
0.070
0.169
SD
0.7126
0.6182
0.5083
0.6195
0.5740
0.9904
Median
0.009
0.082
-0.023
0.021
0.001
0.121
Min.
-0.91
-2.34
-2.28
-2.31
-1.77
-2.25
Max.
4.49
1.61
2.02
2.51
1.88
6.45
Day 28
80
-0.057
0.5081
0.018
-1.35
1.26
82
-0.083
1.1318
0.005
-7.48
2.70
86
0.074
0.9454
0.084
-4.86
2.35
91
0.084
0.8351
0.062
-4.40
2.76
91
0.082
1.2058
0.169
-5.82
7.15
YM2008/00019/00
B2C109575
87
0.091
0.5082
0.063
-1.29
1.28
CONFIDENTIAL
803
n
Mean
SD
Median
Min.
Max.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.69
Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
82
83
88
87
91
92
Mean
-0.089
-0.064
-0.013
0.100
0.050
0.049
SD
0.6907
0.8699
0.7006
1.1355
0.7116
0.7074
Median
-0.011
0.004
-0.038
0.000
0.122
0.062
Min.
-4.03
-5.38
-2.44
-1.68
-4.24
-4.15
Max.
1.76
1.55
2.93
8.31
1.41
2.13
CONFIDENTIAL
804
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.70
Statistical Analysis of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
97
94
95
94
94
LS Mean Change (SE) -0.31 (0.041) -0.29 (0.039) -0.28 (0.040) -0.30 (0.040) -0.24 (0.040) -0.28 (0.040)
Column vs Placebo
Difference
95% C.I.
p-value
0.02
(-0.10, 0.13)
0.778
0.03
(-0.08, 0.14)
0.605
0.00
(-0.11, 0.11)
0.970
0.06
(-0.05, 0.18)
0.264
0.03
(-0.09, 0.14)
0.631
CONFIDENTIAL
805
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.70
Statistical Analysis of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
77
78
84
84
86
90
LS Mean Change (SE) -0.18 (0.037) -0.23 (0.037) -0.32 (0.036) -0.27 (0.036) -0.25 (0.035) -0.32 (0.035)
Column vs Placebo
Difference
95% C.I.
p-value
-0.05
(-0.16, 0.05)
0.312
-0.14
-0.09
(-0.24, -0.04) (-0.19, 0.01)
0.006
0.080
-0.07
(-0.17, 0.03)
0.185
-0.14
(-0.25, -0.04)
0.005
CONFIDENTIAL
806
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.71
Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
81
89
89
89
88
91
LS Mean Change (SE) -0.41 (0.042) -0.37 (0.040) -0.39 (0.040) -0.39 (0.040) -0.35 (0.040) -0.40 (0.039)
Column vs Placebo
Difference
95% C.I.
p-value
0.04
(-0.08, 0.15)
0.520
0.02
(-0.09, 0.13)
0.717
0.03
(-0.09, 0.14)
0.649
0.06
(-0.05, 0.17)
0.296
0.01
(-0.10, 0.12)
0.837
CONFIDENTIAL
807
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.71
Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
78
82
87
84
86
91
LS Mean Change (SE) -0.29 (0.040) -0.40 (0.039) -0.39 (0.038) -0.38 (0.039) -0.39 (0.038) -0.46 (0.037)
Column vs Placebo
Difference
95% C.I.
p-value
-0.11
(-0.22, 0.00)
0.052
-0.11
(-0.22, 0.00)
0.054
-0.09
(-0.20, 0.02)
0.099
-0.11
(-0.22, 0.00)
0.049
-0.17
(-0.28, -0.06)
0.002
CONFIDENTIAL
808
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.72
Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
100
100
100
99
101
99
LS Mean Change (SE)
0.50
0.36 (0.087)
0.25 (0.087)
0.30 (0.088)
0.54 (0.087)
0.50 (0.088)
(0.087)
Column vs Placebo
Difference
95% C.I.
p-value
-0.14
(-0.38, 0.10)
0.259
-0.25
-0.19
(-0.49, -0.01) (-0.43, 0.05)
0.044
0.122
0.05
(-0.20, 0.29)
0.707
0.00
(-0.25, 0.24)
0.996
CONFIDENTIAL
809
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.72
Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
85
83
90
87
93
94
LS Mean Change (SE) 0.37 (0.114)
0.31 (0.115)
0.42 (0.110)
0.43 (0.112)
0.57 (0.108)
0.57 (0.108)
Column vs Placebo
Difference
95% C.I.
p-value
-0.06
(-0.38, 0.26)
0.716
0.05
(-0.27, 0.36)
0.776
0.06
(-0.26, 0.37)
0.723
0.20
(-0.11, 0.50)
0.213
0.20
(-0.11, 0.50)
0.214
CONFIDENTIAL
810
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.73
Statistical Analysis of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
79
93
90
84
87
89
LS Mean Change (SE) 0.036
-0.005
0.032
0.032
0.069
-0.095
(0.0469)
(0.0433)
(0.0439)
(0.0454)
(0.0445)
(0.0445)
Column vs Placebo
Difference
95% C.I.
-0.004
(-0.130,
0.122)
0.954
-0.003
(-0.132,
0.125)
0.959
0.033
(-0.093,
0.160)
0.607
-0.130
(-0.258,
-0.002)
0.046
811
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
p-value
-0.041
(-0.166,
0.085)
0.528
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.73
Statistical Analysis of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
69
70
76
78
77
86
LS Mean Change (SE) 0.094
0.084
-0.006
-0.034
0.084
0.010
(0.0525)
(0.0522)
(0.0500)
(0.0493)
(0.0497)
(0.0472)
Column vs Placebo
Difference
95% C.I.
-0.100
(-0.243,
0.042)
0.167
-0.128
(-0.270,
0.014)
0.077
-0.010
(-0.153,
0.132)
0.885
-0.084
(-0.224,
0.056)
0.237
812
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
p-value
-0.011
(-0.156,
0.134)
0.883
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.74
Statistical Analysis of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
75
87
85
84
81
82
LS Mean Change (SE) -0.188
-0.176
-0.202
-0.184
-0.135
-0.214
(0.0465)
(0.0432)
(0.0435)
(0.0439)
(0.0447)
(0.0445)
Column vs Placebo
Difference
95% C.I.
-0.014
(-0.139,
0.111)
0.827
0.004
(-0.122,
0.131)
0.947
0.053
(-0.074,
0.180)
0.410
-0.025
(-0.152,
0.102)
0.699
813
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
p-value
0.012
(-0.113,
0.137)
0.849
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.74
Statistical Analysis of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
72
75
86
77
82
85
LS Mean Change (SE) -0.066
-0.192
-0.191
-0.158
-0.192
-0.236
(0.0469)
(0.0460)
(0.0428)
(0.0452)
(0.0437)
(0.0434)
Column vs Placebo
Difference
95% C.I.
-0.125
(-0.250,
0.000)
0.050
-0.092
(-0.221,
0.036)
0.159
-0.126
(-0.252,
0.000)
0.050
-0.170
(-0.297,
-0.044)
0.009
814
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
CONFIDENTIAL
p-value
-0.126
(-0.256,
0.003)
0.056
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 8.75
Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
97
98
99
94
99
98
LS Mean Change (SE) 0.117
0.010
-0.069
0.005
0.064
0.183
(0.0616)
(0.0614)
(0.0608)
(0.0623)
(0.0606)
(0.0613)
Column vs Placebo
Difference
95% C.I.
-0.185
(-0.355,
-0.015)
0.033
-0.111
(-0.283,
0.061)
0.204
-0.053
(-0.222,
0.117)
0.543
0.066
(-0.106,
0.238)
0.451
815
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
CONFIDENTIAL
p-value
-0.107
(-0.278,
0.065)
0.222
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 8.75
Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4 hrs)
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
80
82
87
86
91
91
LS Mean Change (SE) -0.045
-0.041
-0.009
0.099
0.068
0.123
(0.0790)
(0.0777)
(0.0756)
(0.0758)
(0.0738)
(0.0737)
Column vs Placebo
Difference
95% C.I.
0.036
(-0.179,
0.251)
0.741
0.144
(-0.072,
0.359)
0.191
0.113
(-0.100,
0.325)
0.298
0.168
(-0.046,
0.381)
0.123
816
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.
CONFIDENTIAL
p-value
0.004
(-0.214,
0.223)
0.968
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 8.76
Summary of Subjects with Asthma Exacerbations
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Any Asthma Exacerbations
4 (4%)
7 (7%)
2 (2%)
0
3 (3%)
1 (<1%)
1 (<1%)
1 (<1%)
Corticosteroids or Hospitalised or ER
(2%)
(2%)
817
0
0
0
0
1
0
1
0
0
0
1
0
1
0
0
0
0
0
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
1 (<1%)
(2%)
1 (<1%)
(5%)
1 (<1%)
(2%)
(2%)
1 (<1%)
1 (<1%)
0
2 (2%)
0
3 (3%)
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
(2%)
YM2008/00019/00
B2C109575
(3%)
CONFIDENTIAL
CONFIDENTIAL
YM2008/00019/00
B2C109575
818
819
824
827
831
834
835
CONFIDENTIAL
CONFIDENTIAL
Figure 9.1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
819
CONFIDENTIAL
CONFIDENTIAL
Figure 9.1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Figure 9.1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Figure 9.1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Figure 9.1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
823
CONFIDENTIAL
Figure 9.2
YM2008/00019/00
B2C109575
Scatter Plot of Individual Observed GW642444 Cmax (2-30mins post-dose) vs Patient Demographics : Age
CONFIDENTIAL
824
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.2
YM2008/00019/00
B2C109575
Scatter Plot Of Individual GW642444 Observed Cmax (2-30mins post-dose) vs Patient Demographics: Weight
CONFIDENTIAL
825
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.2
YM2008/00019/00
B2C109575
Scatter Plot of Individual Observed GW642444 Cmax (2-30mins post-dose) vs Patient Demographics : BMI
CONFIDENTIAL
826
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: PK Concentration
Page 1 of 4
Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009
Analyte: GW642444
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
98/99 (99%)
96/99 (97%)
98/100 (98%)
97/98 (99%)
488/495 (99%)
2 - 10 M
95/98 (97%)
82/98 (84%)
48/99 (48%)
21/99 (21%)
12/96 (13%)
258/490 (53%)
10 - 30 M
97/98 (99%)
92/99 (93%)
65/97 (67%)
40/98 (41%)
10/98 (10%)
304/490 (62%)
30 M - 2 H 100/100 (100%) 96/99 (97%)
89/97 (92%)
73/98 (74%)
19/96 (20%)
377/490 (77%)
2 H - 4 H
98/98 (100%)
98/100 (98%)
93/97 (96%)
92/98 (94%)
56/96 (58%)
437/489 (89%)
PRE-DOSE 1
827
93/93 (100%)
92/93 (99%)
93/95 (98%)
90/93 (97%)
83/93 (89%)
451/467 (97%)
DAY 14 2 M - 1 H
75/83 (90%)
57/90 (63%)
34/91 (37%)
24/91 (26%)
21/90 (23%)
211/445 (47%)
DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
80/81
71/81
77/82
81/82
80/80
88/89
51/89
77/88
89/89
87/87
85/89
18/88
37/85
77/86
83/87
83/89 (93%)
9/90 (10%)
18/91 (20%)
42/87 (48%)
72/92 (78%)
86/93 (92%)
9/94 (10%)
3/92 (3%)
3/95 (3%)
17/92 (18%)
422/441
158/442
212/438
292/439
339/438
(99%)
(88%)
(94%)
(99%)
(100%)
(99%)
(57%)
(88%)
(100%)
(100%)
(96%)
(20%)
(44%)
(90%)
(95%)
(96%)
(36%)
(48%)
(67%)
(77%)
CONFIDENTIAL
DAY 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: PK Concentration
Page 2 of 4
Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009
Analyte: Triphenylacetate
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 98/98 (100%)
96/96 (100%)
99/99 (100%)
100/100 (100%) 100/100 (100%) 493/493 (100%)
2 - 10 M
97/97 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
96/98 (98%)
490/492 (>99%)
10 - 30 M
98/98 (100%)
99/100 (99%)
99/99 (100%)
98/98 (100%)
99/99 (100%)
493/494 (>99%)
30 M - 2 H 97/98 (99%)
100/100 (100%) 97/97 (100%)
100/100 (100%) 97/97 (100%)
491/492 (>99%)
2 H - 4 H
98/98 (100%)
98/98 (100%)
96/96 (100%)
99/99 (100%)
96/97 (99%)
487/488 (>99%)
PRE-DOSE 1
828
86/86 (100%)
88/88 (100%)
80/80 (100%)
86/86 (100%)
83/83 (100%)
423/423 (100%)
DAY 14 2 M - 1 H
82/83 (99%)
89/89 (100%)
91/91 (100%)
92/92 (100%)
90/91 (99%)
444/446 (>99%)
DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
81/81
81/81
81/82
81/81
81/81
90/90
89/90
90/91
90/90
88/89
89/89
85/86
88/88
86/87
87/87
92/92
90/90
91/91
92/92
91/91
97/97
90/95
95/95
96/97
92/94
449/449
435/442
445/447
445/447
439/442
(100%)
(100%)
(99%)
(100%)
(100%)
(100%)
(99%)
(99%)
(100%)
(99%)
(100%)
(99%)
(100%)
(99%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(95%)
(100%)
(99%)
(98%)
(100%)
(98%)
(>99%)
(>99%)
(>99%)
CONFIDENTIAL
DAY 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: PK Concentration
Page 3 of 4
Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009
Analyte: GW630200
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
99/99 (100%)
99/99 (100%)
101/101 (100%) 101/101 (100%) 499/499 (100%)
2 - 10 M
98/98 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
97/97 (100%)
492/492 (100%)
10 - 30 M
98/98 (100%)
99/99 (100%)
98/98 (100%)
98/98 (100%)
99/99 (100%)
492/492 (100%)
30 M - 2 H 100/100 (100%) 99/99 (100%)
97/97 (100%)
98/98 (100%)
96/96 (100%)
490/490 (100%)
2 H - 4 H
98/98 (100%)
100/100 (100%) 97/97 (100%)
98/98 (100%)
96/96 (100%)
489/489 (100%)
PRE-DOSE 1
829
93/93 (100%)
94/94 (100%)
95/95 (100%)
95/95 (100%)
95/95 (100%)
472/472 (100%)
DAY 14 2 M - 1 H
83/83 (100%)
90/90 (100%)
90/91 (99%)
91/91 (100%)
92/92 (100%)
446/447 (>99%)
DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
81/81
81/81
82/82
82/82
80/80
89/89
89/89
88/88
90/90
87/87
89/89
88/88
88/88
88/88
87/87
91/91
91/91
91/91
90/90
92/92
93/93
94/94
93/93
96/96
93/93
443/443
443/443
442/442
446/446
439/439
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
CONFIDENTIAL
DAY 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: PK Concentration
Page 4 of 4
Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009
Analyte: GSK932009
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
98/98 (100%)
99/99 (100%)
101/101 (100%) 101/101 (100%) 498/498 (100%)
2 - 10 M
98/98 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
96/96 (100%)
491/491 (100%)
10 - 30 M
97/97 (100%)
99/99 (100%)
98/98 (100%)
99/99 (100%)
99/99 (100%)
492/492 (100%)
30 M - 2 H 99/99 (100%)
99/99 (100%)
97/97 (100%)
98/98 (100%)
96/96 (100%)
489/489 (100%)
2 H - 4 H
98/98 (100%)
100/100 (100%) 96/96 (100%)
98/98 (100%)
96/96 (100%)
488/488 (100%)
PRE-DOSE 1
830
93/93 (100%)
94/94 (100%)
95/95 (100%)
96/96 (100%)
95/95 (100%)
473/473 (100%)
DAY 14 2 M - 1 H
83/83 (100%)
90/90 (100%)
91/91 (100%)
91/91 (100%)
92/92 (100%)
447/447 (100%)
DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
81/81
81/81
82/82
82/82
81/81
89/89
89/89
88/88
90/90
88/88
89/89
88/88
88/88
88/88
87/87
91/91
91/91
91/91
90/90
92/92
92/93
93/94
91/92
95/96
92/93
442/443
442/443
440/441
445/446
440/441
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(100%)
(99%)
(99%)
(99%)
(99%)
(99%)
(>99%)
(>99%)
(>99%)
(>99%)
(>99%)
CONFIDENTIAL
DAY 7
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: PK Concentration
Page 1 of 3
Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------3mcg
100 DAY 1
PRE-DOSE 1
99
99
NQ
NQ - NQ
2 - 10 M
98
95
NQ
NQ - 36.70
10 - 30 M
98
97
NQ
NQ - 165.60
30 M - 2 H 100
100
NQ
NQ - NQ
2 H - 4 H
98
98
NQ
NQ - NQ
93
NQ
NQ - NQ
DAY 14
2 M - 1 H
83
75
NQ
NQ - 58.10
DAY 28
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
81
81
82
82
80
80
71
77
81
80
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
54.70
90.80
201.60
31.00
NQ
6.25mcg
101
DAY 1
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
99
98
99
99
100
98
82
92
96
98
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
173.30
121.70
108.60
81.70
109.10
DAY 7
PRE-DOSE 1
93
92
NQ
NQ - 196.40
DAY 14
2 M - 1 H
90
57
NQ
NQ - 166.30
DAY 28
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
89
89
88
89
87
88
51
77
89
87
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
71.60
96.60
170.00
NQ
NQ
CONFIDENTIAL
93
YM2008/00019/00
B2C109575
PRE-DOSE 1
831
DAY 7
Protocol: B2C109575
Population: PK Concentration
Page 2 of 3
Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------12.5mcg
100 DAY 1
PRE-DOSE 1
99
96
NQ
NQ - 144.20
2 - 10 M
99
48
31.500 NQ - 111.50
10 - 30 M
97
65
NQ
NQ - 215.10
30 M - 2 H
97
89
NQ
NQ - 65.70
2 H - 4 H
97
93
NQ
NQ - 126.30
93
NQ
NQ - 180.50
DAY 14
2 M - 1 H
91
34
43.600
NQ - 305.10
DAY 28
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
89
88
85
86
87
85
18
37
77
83
NQ
55.450
35.400
NQ
NQ
NQ
NQ
NQ
NQ
NQ
172.40
169.10
200.30
79.30
98.30
25mcg
101
DAY 1
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
100
99
98
98
98
98
21
40
73
92
NQ
60.200
36.500
NQ
NQ
NQ
NQ
NQ
NQ
NQ
60.20
260.70
188.40
106.50
76.70
DAY 7
PRE-DOSE 1
93
90
NQ
NQ - 132.30
DAY 14
2 M - 1 H
91
24
66.300
NQ - 324.90
DAY 28
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
89
90
91
87
92
83
9
18
42
72
NQ
120.650
61.400
30.200
NQ
NQ
NQ
NQ
NQ
NQ
171.90
328.10
236.30
107.00
186.60
CONFIDENTIAL
95
YM2008/00019/00
B2C109575
PRE-DOSE 1
832
DAY 7
Protocol: B2C109575
Population: PK Concentration
Page 3 of 3
Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------50mcg
102 DAY 1
PRE-DOSE 1
98
97
NQ
NQ - 104.40
2 - 10 M
96
12 127.400 NQ - 623.60
10 - 30 M
98
10 113.400 NQ - 587.70
30 M - 2 H
96
19
57.350 NQ - 177.80
2 H - 4 H
96
56
NQ
NQ - 92.90
PRE-DOSE 1
93
83
DAY 14
2 M - 1 H
90
21
166.050
NQ - 701.50
DAY 28
PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H
93
94
92
95
92
86
9
3
3
17
NQ
249.800
140.600
71.800
42.450
NQ
NQ
NQ
NQ
NQ
NQ - 505.90
555.30
975.60
516.10
270.90
161.00
YM2008/00019/00
B2C109575
NQ
CONFIDENTIAL
833
DAY 7
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Table 9.3
Summary GW642444 Cmax and tmax (estimated over period 2-10
mins post-dose)
Parameter
(units)
Cmax
(pg/mL)
tmax (h)
Dose
(g)
3
Visit
n*
2
5
100
82
100
82
96
69
Geometric
Mean
NA
NA
6.25
2
5
101
90
96
88
79
50
12.5
2
5
100
89
97
86
25
2
5
101
92
50
2
5
2
5
6.25
95% CI
Median
Range
NA
NA
NC
NC
NC - 165.6
NC - 201.6
NA
NA
NA
NA
NC
NC
NC 121.7
NC - 170.0
40
14
NA
NA
NA
NA
41.0
59.5
NC - 215.1
NC 200.3
98
91
17
9
59.3
95.4
50.5 - 69.7
81.1 112.2
64.8
119.6
NC - 260.7
NC - 328.1
102
97
100
82
93
89
4
13
6
3
96
69
139.1
223.0
ND
ND
117.8 164.1
189.6 262.4
ND
ND
142.1
267.4
0.15
0.15
NC - 623.6
NC - 975.6
0.05 - 0.48
0.05 - 0.50
2
5
101
90
17
38
79
50
ND
ND
ND
ND
0.20
0.17
0.05 - 0.42
0.05 - 0.37
12.5
2
5
100
89
57
72
40
14
ND
ND
ND
ND
0.17
0.17
0.03 - 0.45
0.03 - 0.45
25
2
5
101
92
81
82
17
9
ND
ND
ND
ND
0.17
0.17
0.03 - 0.53
0.05 - 0.47
0.17
ND
ND
6
87
102
2
0.05 0.52
0.17
ND
ND
3
86
97
5
0.05 - 0.48
NC =non calculable due to NQ concentrations
NA = not applicable due to insufficient data to derive summary measure
n = Number of subjects with non-missing values (including NC values)
n* = Number of subjects for whom parameter cannot be derived because of NQ concentrations, NCs were imputed
prior to derivation of summary statistics; No NC values were computed for tmax. Cmax imputed with LLQ (15
pg/mL).
50
834
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Table 9.4
Visit 2 (Day1)
Males (M)
Females (F)
Visit 5 (Day28)
Males (M)
Females (F)
STRATA
Visit 2 (Day1)
Lower (L)
(65-90)
Upper (U)
(40-65)
Visit 5 (Day28)
Lower (L)
(65-90)
Upper (U)
(40-65)
12.5 g GW642444
(M44/F56)
42.6
[NC-98.8]
39.6
[NC-215.1]
12.5 g
(M37/F52)
62
[NC-200.3]
59.5
[NC-128.5]
25 g GW642444
(M40/F61)
47.5
[NC-133.3]
74.8
[NC-260.7]
25 g
(M36/F57)
98.4
[NC-325.9]
127
[NC-328.1]
50 g GW642444
(M45/F56)
133.6
[NC-412.4]
158.1
[NC-623.6]
50 g
(M44/F53)
215.1
[NC-647.4]
287.1
[NC-975.6]
12.5 g
(L58/U42)
47.8
[NC-215.1]
NC
[NC-98.8]
12.5 g
(L53/U36)
62.7
[NC-169.1]
49.5
[NC-200.3]
25 g
(L54/U47)
88.4
[NC-208.3]
44.2
[NC-260.7]
25 g
(L50/F43)
127.7
[NC-256.4]
92.3
[NC-328.1]
50 g
(L56/U45)
186.5
[NC-623.6]
131.0
[NC-423.4]
50 g
(U49/F40)
271.3
[NC-975.6]
266.9
[NC-471.9]
835
CONFIDENTIAL
YM2008/00019/00
B2C109575
836
837
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
CONFIDENTIAL
Figure 9.3
YM2008/00019/00
B2C109575
Scatter Plots Of Systemic PD Endpoints versus GW642444 Cmax (2-30mins post-dose): Pulse Rate
CONFIDENTIAL
837
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.3
YM2008/00019/00
B2C109575
Scatter Plots of Systemic PD Endpoints versus GW642444 Cmax (2-30mins post-dose): QTc(B)
CONFIDENTIAL
838
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.3
YM2008/00019/00
B2C109575
Scatter Plots of Systemic PD Endpoints and GW642444 Cmax (2-30mins post-dose): QTc(F)
CONFIDENTIAL
839
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.3
YM2008/00019/00
B2C109575
Scatter Plot of Systemic PD Endpoints and GW642444 Cmax (2-30mins post-dose): Fasting Potassium
CONFIDENTIAL
840
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.3
YM2008/00019/00
B2C109575
Scatter Plots of Systemic PD endpoints versus GW642444 Cmax (2-30mins post-dose): Glucose
CONFIDENTIAL
841
YM2008/00019/00
B2C109575
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.4
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]
10
20
30
OD Dose (ug)
Source data: Figure 9.4
842
40
50
CONFIDENTIAL
Figure D.4
YM2008/00019/00
B2C109575
843
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.6
0.40
Day 28 Placebo
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
0
10
12
14
16
18
20
22
24
26
Time (h)
0.40
Day 28 25ug
0.35
0.30
0.25
LSMean Obs
Mean model
0.20
0.15
0.10
0.05
0.00
-0.05
0
10
12
14
16
18
20
Time (h)
844
22
24
26
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.7
K-PD model based simulations of time course of FEV1 for placebo and
od versus bid GW642444 at steady state
0.50
'444 12.5ug bd
'444 25ug od
Obs Placebo '575
Modelled Placebo '575
0.45
0.40
0.35
0.30
0.25
0.20
0.15
plac obs
plac simulate
0.10
0.05
0.00
0
10
12
14
16
845
18
20
22
24
26
YM2008/00019/00
B2C109575
CONFIDENTIAL
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3
0.30
0.25
Threshold Max HR
0.20
0.15
0.10
0.05
Max HR
0.00
-0.05
0
10
20
30
OD Dose (ug)
Source data: Figure 9.8
846
40
50
Figure 9.8
CONFIDENTIAL
Figure 9.9
YM2008/00019/00
B2C109575
This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
847
CONFIDENTIAL
Figure 9.10
848
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.11
YM2008/00019/00
B2C109575
849
CONFIDENTIAL
Figure 9.12
YM2008/00019/00
B2C109575
850
CONFIDENTIAL
Figure 9.13
851
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.14
852
YM2008/00019/00
B2C109575
CONFIDENTIAL
Figure 9.15
YM2008/00019/00
B2C109575
853
CONFIDENTIAL
Figure 9.16
YM2008/00019/00
B2C109575
This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available subject to
an approved research proposal. For further information please see the Patient Level Data section of the
GSK Clincal Study Register.
854
CONFIDENTIAL
Figure 9.17
YM2008/00019/00
B2C109575
This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
855
CONFIDENTIAL
Figure 9.18
YM2008/00019/00
B2C109575
This section contained data from each individual patient, rather than in aggregate. They
have been excluded to protect patient privacy. Anonymized data from each patient may be
made available subject to an approved research proposal. For further information please
see the Patient Level Data section of the GSK Clincal Study Register.
856
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Table 9.5
Dose Response Model Parameters for trough FEV1 change from
Baseline on Day 28 (ITT Population Model)
Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error
Value
% RSE
0.243
20
16.1
11
0.733
18
-0.392
12
2.65
21
-0.166
24
Proportional: CV 12%
Additive: Standard Deviation 0.1
857
5th CI
0.149
12.5
0.480
-0.482
1.57
-0.245
95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087
CONFIDENTIAL
CONFIDENTIAL
Table 9.6
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
Expected response
37
68
106
148
184
858
CONFIDENTIAL
CONFIDENTIAL
Table 9.7
Dose (g)
3
6.25
12.5
25
50
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
Probability (%) that a Certain Dose Will Exceed the Target Response
(OD Dosing)
100 mL
5
19
56
90
99
859
200 mL
0
0
0.7
9
33
CONFIDENTIAL
CONFIDENTIAL
Table 9.8
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
Parameters
Value
Rm (L)
14.7
Baseline effect on Rm
0.414
Tz (h)
0.041
Tz1 (h)
2.41
Ramp
0.033
Ramp1
0.014
Kout (1/h)
16.1
EDK50 (ug)
15.9
Kde (1/h)
0.027
Emax (L)
0.275
Inter-patient variability
()
Value (CV%)
0.102 (32%)
Rm
8.99 (300%)
Tz
0.339 (58%)
Tz1
0.392 (63%)
Ramp
0.736 (86%)
Ramp1
0.149 (39%)
Kout
2.99 (173%)
EDK50
1.38 (117)
kde
0.358 (60%)
Ka
1.30 (114%)
Emax
Residual error (additive)
Value (SD)
0.131
860
r.s.e. (%)
2
2
39
1
2
3
1
13
6
6
r.s.e.(%)
4
1
3
3
3
3
3
3
3
3
r.s.e.(%)
1
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Table 9.9
Model
1
Description
Step
Step-Linear
Emax
Emax
Sigmoid Emax
Parameter
1 (L)
2
1
2
1
1
2
3
2
1
1
2
3
1
2
3
1
2
1
2
3
1
1
2
1
2
3
1
Gam
1
2
Definition
Intercept
Dose effect
Baseline variability
Drug eff. variab. shift
Additive error
Value
2.24
0.177
30%
105%
0.0527
Intercept
Dose effect
Slope D-R
Ind. Baseline shift
Additive error
OFV
245
Comments
FOCEI
Successful
Covariance
2.42
0.132
0.0022
31%
0.045
243
FOCEI
No
Covariance
Intercept
Emax
ED50
Indiv baseline shift
Indiv shift ED50
Indiv shift Emax
Additive Error
Exponential
2.22
0.236
2.95
29%
10%
0.10%
0.0705
0
240
FOCEI
No
Covariance
Overparameterise
Intercept
Emax
ED50
Indiv baseline shift
Additive Error
Exponential
2.22
0.236
0.295
29%
0.266
9%
240
FOCEI
Successful
Covariance
High Error on
ED50
Intercept
Emax
ED50
Indiv baseline shift
Slope of D-R
Additive Error
Exponential
0.343
0.15
3.96
89%
0.0128
0.01
26%
230
FOCEI
No
Covariance
861
SE(%)
3.4
46
10
50
3
46
147
14
39
42
YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575
CONFIDENTIAL
CONFIDENTIAL
Table 9.10
Model
Description
Parameter
Definition
Value
SE
(%)
OFV
Comments
Model #4
Age on 1
Model #4
Base on 1
Model #4
Gender on 1
Model #4
Full Model
_age
Age on 1
-0.008
4.1
11.5
_base
Base on 1
5.18
-631
_gender
Gender on 1
-0.27
89
_age
_base
_gender
_gender
_base
_age
_gender
_age
_base
_age
_base
_gender
Age on 1
Base on 1
Gender on 1
Gender on 1
Base on 1
Age on 1
Gender on 1
Age on 1
Base on 1
Age on 1
Base on 1
Gender on 1
-0.39
2.65
-0.166
18
21
24
-
-688
FOCE1
Covariance OK
FOCE1
No Covariance
FOCE1
Covariance OK
FOCE1
Covariance OK
7
8
9
10
12
13
14
Model #4
Reduced Model
Model #4
Reduced Model
Model #4
Reduced Model
Model #9
Final Model
ED50=0
862
-0.32
-0.166
-0.488
4.26
-0.453
2.91
-0.188
-637
-674
14
24
26
-675
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
Covariance OK
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Table 9.11
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Dose (g)
0
3
6.25
12.5
25
50
86
83
90
88
89
98
6.9
13.6
20.9
19.5
23
22.6
95th CI Median
5th
4.2
10.9
18.2
17.1
20.6
20.2
863
95th
9.6
16.3
23.6
22.0
25.4
25.0
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Placebo
Total
n=102
84 (82)
3 g
GW642444M
n=101
79 (78)
6.25 g
GW642444M
n=101
76 (75)
12.5 g
GW642444M
n=100
86 (86)
25 g
GW642444M
n=101
78 (77)
50 g
GW642444
n=102
82 (80)
Respiratory,
thoracic and
mediastinal
disorders
Nervous system
disorders
Musculoskeletal
and connective
tissue disorders
Hypersensitivity /
anaphylaxis
related
Gastrointestinal
disorders
Immune system
disorders
Cardiac disorders
45 (44)
38 (38)
41 (41)
49 (49)
36 (36)
48 (47)
23 (23)
15 (15)
23 (23)
20 (20)
22 (22)
21 (21)
20 (20)
23 (23)
20 (20)
26 (26)
16 (16)
18 (18)
20 (20)
15 (15)
15 (15)
15 (15)
17 (17)
25 (25)
107
(18)
16 (16)
12 (12)
12 (12)
19 (19)
13 (13)
17 (17)
9 (9)
21 (21)
12 (12)
15 (15)
13 (13)
16 (16)
14 (14)
18 (18)
13 (13)
11 (11)
15 (15)
13 (13)
Skin and
subcutaneous
tissue disorders
Eye disorders
Vascular
disorders
Endocrine
disorders
Psychiatric
disorders
Metabolism and
nutrition disorders
Blood and
lymphatic system
disorders
Ear and labyrinth
disorders
Renal and urinary
disorders
Neoplasms
benign, malignant
and unspecified
(incl cysts and
polyps)
Infections and
infestations
Source Table 6.14.
13 (13)
16 (16)
7 (7)
12 (12)
9 (9)
16 (16)
89
(15)
86
(14)
84
(14)
73
(12)
10 (10)
13 (13)
5 (5)
5 (5)
11 (11)
8 (8)
11 (11)
11 (11)
8 (8)
10 (10)
12 (12)
9 (9)
57 (9)
56 (9)
10 (10)
8 (8)
10 (10)
5 (5)
4 (4)
12 (12)
49 (8)
8 (8)
6 (6)
5 (5)
8 (8)
4 (4)
6 (6)
37 (6)
7 (7)
5 (5)
5 (5)
6 (6)
9 (9)
5 (5)
37 (6)
4 (4)
3 (3)
3 (3)
5 (5)
6 (6)
21 (3)
5 (5)
1 (<1)
3 (3)
3 (3)
2 (2)
6 (6)
20 (3)
5 (5)
1 (<1)
3 (3)
6 (6)
2 (2)
1 (<1)
18 (3)
2 (2)
2 (2)
1 (<1)
2 (2)
1 (<1)
8 (1)
1 (<1)
2 (2)
3 (<1)
Any condition
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485
(80)
257
(42)
124
(20)
123
(20)
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N
100a
Visit
(Day +4/-2)
2 (Day 1)
3 (Day 7)
4 (Day 14)
5 (Day 28)
6.25
101
2 (Day 1)
3 (Day 7)
4 (Day 14)
5 (Day 28)
12.5
100
2 (Day 1)
3 (Day7)
4 (Day14)
5 (Day 28)
Time
n*
Median
Range
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
99
98
98
100
98
93
83
81
81
82
82
80
99
95
97
100
98
93
75
80
71
77
81
80
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ - 36.7
NQ - 165.6
NQ
NQ
NQ
NQ - 58.1
NQ - 54.7
NQ - 90.8
NQ - 201.6
NQ - 31
NQ
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
99
98
99
99
100
93
90
89
89
88
89
87
98
82
92
96
98
92
57
88
51
77
89
87
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ - 173.3
NQ - 121.7
NQ - 108.6
NQ - 81.7
NQ - 109.1
NQ - 196.4
NQ - 166.3
NQ - 71.6
NQ - 96.6
NQ - 170
NQ
NQ
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
99
99
97
97
97
95
91
89
88
85
86
87
96
48
65
89
93
93
34
85
18
37
77
83
NQ
31.5
NQ
NQ
NQ
NQ
43.6
NQ
55.5
33.4
NQ
NQ
NQ-144.2
NQ - 111.5
NQ - 215.1
NQ - 65.7
NQ - 126.3
NQ-180.5
NQ - 305.1
NQ-172.4
NQ - 169.1
NQ - 200.3
NQ - 79.3
NQ - 98.3
Continued
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101
2 (Day 1)
3 (Day7)
4 (Day14)
5 (Day 28)
50
102
2 (Day 1)
3 (Day7)
4 (Day14)
5 (Day 28)
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
100
99
98
98
98
93
91
89
90
91
87
92
98
21
40
73
92
90
24
83
9
18
42
72
NQ
60.2
36.5
NQ
NQ
NQ
66.3
NQ
120.7
61.4
30.2
NQ
NQ - 60.2
NQ - 260.7
NQ - 188.4
NQ - 106.5
NQ 76.7
NQ - 132.3
NQ - 324.9
NQ - 171.9
NQ - 328.1
NQ - 236.3
NQ - 107
NQ - 186.6
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
98
96
98
96
96
93
90
93
94
92
95
92
97
12
10
19
56
83
21
86
9
3
3
17
NQ
127.4
113.4
57.4
NQ
NQ
166.1
NQ
249.8
140.6
71.8
42.5
NQ - 104.4
NQ - 623.6
NQ - 587.7
NQ - 177.8
NQ - 92.9
NQ - 505.9
NQ -701.5
NQ - 555.3
NQ - 975.6
NQ - 516.1
NQ - 270.9
NQ-161.0
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1 = placebo effect
Q1 j = 0 if dose =0
2 (change in FEV1 response due to drug regardless of dose, i.e , maximum effect,
Emax), otherwise
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The step linear model states that a given response occurs with the lowest dose of drug and
there is a further additional response that increases linearly as dose increases.
Step-linear model:
FEV1,ij = 1 (1 + 1 j ) + Q1 j + (3 Doseij ) (1 + 2 j ) + ij
Q1 j = 0 if dose =0
ik = pop ,k exp(ik )
where pop ,k is the mean population parameter of the kth element and ik represents the
shift in the parameter of the ith individual from the population mean. ik was further
assumed to be independent multivariate normally distributed, with mean 0 and variance
(2) to be estimated
For residual error in the population dose-response analysis, additive, proportional and
combined additive and exponential error models were tested. is random effect
representing the residual error, that is , the difference between observed and predicted
response for each individual using a combination of exponential and additive error. It is
assumed to be normally distributed with mean zero and a variance (2) to be estimated.
The fit to the different potential dose-response models were compared using the objective
function (OFV) calculated by NONMEM program. The OFV is proportional to the -
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2*log likelihood of the fits and can be used to compare the goodness of fit of the various
models in a sequential manner. A lower OFV value indicates a better fit. For example,
the OFV value obtained after the step-linear model was compared to the reference step
model with the difference between the 2 OFV being 2 distributed. Confidence intervals
on the parameter estimates were obtained from the usual approximate asymptotic
covariance matrix of the estimates.
Covariate models
To assess whether patient factors influenced the dose-response parameters of GW642444,
individual empirical Bayes estimates of the parameters were generated from the basic
model, and plots of the difference between these and the population estimates (the is vs
covariates were constructed to visualise potential relationships. The patient factors
(BASE, AGE, SEX) entered the model through the parameters (E0, Emax, ED50) of the
model using multiplicative equation
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The dose-response model was applied to simulate the dose-response relationship and its
associated uncertainty for the change in LSMean FEV1. The predictive distribution of the
dose-response relationships was derived by sampling 10000 sets of model parameters
from a multivariate normal distribution with mean and variance-covariance matrix
obtained from the above dose-response model. This set of model parameters reflects the
uncertainty in the dose-response model for the drug. The dose-response relationship is
calculated for each set of parameters, yielding a distribution, expressed in percentiles
(pctl), of the likely response as function of dose.
Results
The optimal structural model was the Emax model with inter-subject variance on the
intercept (placebo) parameter. Inclusion of inter-subject variability on the ED50 and
Emax showed over-parameterisation which is expected of parallel-type study design with
1 response per individual (i.e a population instead of individual dose-response can be
estimated). Table D1 summarises the various models and logical selection of the optimal
structural dose-response model.
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Table D1
Model
1
Description
Step
Step-Linear
Emax
Emax
Sigmoid Emax
Parameter
1 (L)
2
1
2
1
1
2
1
2
1
1
2
3
1
2
3
1
2
1
2
3
1
1
2
1
2
3
1
Gam
1
2
Definition
Intercept
Dose effect
Baseline variability
Drug eff. variab. Shift
Additive error
Value
2.24
0.177
30%
105%
0.0527
Intercept
Dose effect
Slope D-R
Ind. Baseline shift
Additive error
SE(%)
3.4
46
10
50
OFV
245
Comments
FOCEI
Succesful
Covariance
2.42
0.132
0.0022
31%
0.045
243
FOCEI
No Covariance
Intercept
Emax
ED50
Indiv baseline shift
Indiv shift ED50
Indiv shift Emax
Additive Error
Exponential
2.22
0.236
2.95
29%
10%
0.10%
0.0705
0
240
FOCEI
No Covariance
Overparameterise
Intercept
Emax
ED50
Indiv baseline shift
Additive Error
Exponential
2.22
0.236
0.295
29%
0.266
9%
240
FOCEI
Succesful
Covariance
High Error on
ED50
Intercept
Emax
ED50
Indiv baseline shift
Slope of D-R
Additive Error
Exponential
0.343
0.15
3.96
89%
0.0128
0.01
26%
3
46
147
14
39
42
FOCEI
No Covariance
Model#4 was the optimal basic structural model and a stepwise forward and backward
selection was performed for each of the covariates on each of the parameter. Age, gender
and baseline appeared most influential in describing the intersubject variability in placebo
response (Model 9 in Table D2).
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Table D2
Model
Description
Parameter
Definition
Value
Model #4
Age on 1
Model #4
Base on 1
Model #4
Gender on 1
Model #4
Full Model
_age
Age on 1
_base
7
8
9
10
Model #4
Reduced Model
12
Model #4
Reduced Model
13
Model #4
Reduced Model
14
Model #9
Final Model
ED50=0
Source data: Table 9.10
OFV
Comments
-0.008
SE
(%)
4.1
11.5
Base on 1
5.18
-631
_gender
Gender on 1
-0.27
89
_age
_base
_gender
_gender
_base
_age
_gender
_age
_base
_age
_base
_gender
Age on 1
Base on 1
Gender on 1
Gender on 1
Base on 1
Age on 1
Gender on 1
Age on 1
Base on 1
Age on 1
Base on 1
Gender on 1
-0.39
2.65
-0.166
18
21
24
-
-688
FOCE1
Covariance OK
FOCE1
No Covariance
FOCE1
Covariance OK
FOCE1
Covariance OK
-0.32
-0.166
-0.488
4.26
-0.453
2.91
-0.188
-637
-674
14
24
26
-675
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
Covariance OK
Based on the parameters of the final model (#9), the coefficients for the covariate effects
suggest that there is a linear inverse relationship between age and placebo response- there
is on average a 0.9% /year decrease in baseline FEV1 values. Females tend to show on
average a 17% lower baseline values compared to males. Higher baseline FEV1 values
are associated with higher placebo response (20% higher placebo response).
When the final E-max model was rerun by fixing ED50 to 0 (model #14 assumes all
active doses are equal), the final Emax model #9 was superior to model #14 as the
loglikelihood ratio (OBJ) increased from -688 (model#9) to -675 (model#14) for
negative LLR, model is better the further it is from 0. The difference of 13 between the
models show significance at p<0.05 implying final Emax model#9 shows a true doseresponse relationship.
Model Diagnostics
Based on the graphical diagnostics (Figure D.1), the Emax model adequately describes
the dose-response relationship. Thus the population and individual predictions track the
observed trough FEV1 data (DV). The individual weighted residuals (IWRES) versus
individual predictions and weighted residuals (WRES) versus dose do not show any
obvious bias (note: Time refers to dose (g) in graph).
More commonly, simulation-based diagnostics known as predictive checks are applied
to illustrate model properties. The visual predictive check (VPC) is a model diagnostic
that can be used to: (i) allow comparison between alternative models, (ii) suggest model
improvements, and (iii) support appropriateness of a model. The VPC is constructed from
stochastic simulations from the model therefore all model components contribute and it
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can help in diagnosing both structural and stochastic contributions. Summary measures of
the distribution of predictions and observations are compared visually. Typical summary
measures are the median and an interval defined by the lower 5% and upper 5% of the
values.
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clincal Study Register.
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Figure D.2
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variability. This figure can therefore be used to evaluate the probability (chance) of
achieving a certain response at a selected dose or to evaluate the probability of a certain
dose to achieve a selected response. For example, from Figure D.4 at 12.5 g dose, the
average response (50th pctl) is estimated at >100mL with 90% chance of the response
being between 45 mL to 167 mL. Table D4 provides the expected responses at the other
doses.
Figure D.3
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]
10
20
30
40
50
OD Dose (ug)
Table D3
Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error
Value
0.243
16.1
0.733
-0.392
2.65
-0.166
Proportional
Additive
% RSE
20
11
18
12
21
24
CV 12%
St Dev 0.16
-9880
5th CL
0.149
12.5
0.48
-0.482
1.57
-0.245
95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087
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Figure D.4
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Table D4
3
6.25
12.5
25
50
Source data : Table 9.6
A different view of the likely dose to achieve a certain response can also be estimated
from the above dose-response model simulations. The probability of a certain dose to
exceed an FEV1 response target can be estimated (Figure D.4 and Table D5). Thus, if the
target response of >100 mL FEV1 at trough is required, there is a 56% chance of
achieving this target response (Table D5).
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Table D5
Dose
(g)
3
6.25
12.5
25
50
Source Table 9.7
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Probability (%) That a Certain Dose Will Exceed the Target Response
(OD Dosing)
100 mL
5
19
56
90
99
Characterise the baseline (placebo) time course of FEV1 that best described the
observed data
Apply population K-PD model to simultaneously model the time course of FEV1 in
the placebo and GW642444M treatment groups.
Evaluate the influence of any patient covariates on the parameters of the K-PD
model
Evaluate predictability of the K-PD model for the 28 day trough FEV1 response and
compare with actual data
Step 1: Model to describe the 24-hour FEV1 profile in placebo (without drug)
Graphical visualisation of time course of LSMean FEV1 (change from baseline and
difference from placebo) by dose show diurnal variations over 24h (Figure D.5) and is
consistent with the well recognised circadian variation in pulmonary function in
asthmatics [Medarov, 2008; Calverley, 2003]. It is therefore important that this diurnal
variation in baseline time course of pulmonary function be adequately characterised to
reliably model and predict the time course of FEV1 after drug treatment only.
Examination of the observed LSMean profile of FEV1 over 24h on day 1 and after
repeated once daily dosing on day 28 in placebo and treatment groups suggests no
marked difference in the diurnal FEV1 profile (Figure D.5).
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Figure D.5
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Given the exploratory graphical analysis, cosine functions were evaluated on the placebo
profiles initially in a subset of 30 patients using day 1 data mainly due to computational
time to enable evaluation a a range of structural models including basic turnover (no
circadian), circadian using single and dual cosine functions as represented below:
n
2 (T 2i +1 exp( 2 i +1 )
Base(t ) = 1 exp(1 ) 1 + 2i exp(2i ) cos
exp( i ) .
24
i =1
883
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The time course of baseline FEV1 (Base(t)) was used as the circadian input for the
turnover rate model with Kout as the turnover rate constant of FEV1 response according
to
dR
= Base Kout R
dt
Step 2: Model to describe the 24-hour FEV1 profile for whole population ( placebo
and drug treatments).
Background on K-PD modelling approach
In the absence of PK information linking with PD effect in target tissue (e.g lung), an
alternative approach can be applied to characterise the time profile of PD marker (e.g
FEV1) as function of dose. Pharmacodynamic response versus time data , even in absence
of drug levels, inherently contain useful information about the turnover characteristics of
response (turnover rate, half-life of response), the drug biophase kinetics (relative
bioavailability, half life) as well as the pharmacodynamic characteristics (potency,
intrinsic activity).
Some of the underlying principles for modelling dose-response-time data and duration of
response have been extensively documented [Gabrielsson, 2000]. The general
applicability of the K-PD model when compared to corresponding PK-PD model (where
plasma kinetics are available) has been extensively studied. Some general requirements
for undertaking this K-PD model include availability of data such as different doses,
different dose regimens (e.g. single dose and repeat dose) and adequate response
measurements over the dosing interval.
It is assumed that the availability of an inhaled dose of GW642444M in the lung (virtual
compartment) will drive the pharmacology, and the duration of effect is driven by the
residency of the drug in equilibrium with the response at the target site receptors. The
product of the amount of drug at a certain time in the lung and its equilibrium rate
constant (KDE) will reflect the dose rate driving the pharmacodynamic effect over time.
The time course of pharmacodynamic response (FEV1) as function of dose, dose regimen
and time provide inherent information about the kinetics of drug action which can be
captured as a physiological E-max type model. Based on the prolonged duration of effect
of the drug, it is assumed an indirect response (turnover) mechanism is driving the
pharmacodynamics through stimulation of production of FEV1 and an offset rate which
are captured by the respective parameter rate constants (KS and KD).
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KDE:
DDR:
EDK50:
:
Emax
A:
Biomarker:
Ks or Kin
Kd or Kout
The corresponding set of differential equations for the structural model are shown below:
dA
= KDE
dt
DDR = A * KDE
dR
= K in K o u t R
dt
K in
R (0 ) =
K out
where R=FEV1 , R(0) = Base
E max DDR
Kin = Base 1 +
EDK 50 + DDR
Base = circadian baseline FEV1 response as described in step1 above
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Statistical Model
yij = f ( i , tij ) + ij
where i denotes the vector of parameter value for individual i , and its components are
assumed to follow a log-normal distribution:
i = *ei
where i ~ N(0,) is the vector of individual random effects where the variance to be
estimated. is the population mean parameter value.
ij 2 = 2 e f
Model selection was based on both the Wald test and likelihood ratio test for nested
models; the final model selected should be the model which gives the smallest objective
function.
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Softwares
Two softwares utilising different maximum likelihood estimation methods for non linear
mixed effects analysis were applied for modelling the time course of FEV1
Other softwares used for data exploration and statistics, analysis-ready datasets,
model diagnostics and clinical trial simulation include R 2.7.0, SAS Version 9,
Xpose V4, Perl-Speaks-Nonmem (PsN) and Pharsight Trial simulator (V 2.2).
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Results
The estimated parameters for the K-PD model showed good precision (Table D6) and
adequately described the FEV1 response data with time based on the model population
and individual predictions which are very close to the line of unity (Figure D.5). During
model development, baseline FEV1 showed highest correlation with the Rm parameter
(rhythm-adjusted mean FEV1) and was used in the basic model structure. Separate
analyses were performed on the time course of FEV1 for day 1 and repeat dose datasets.
As there was no marked deviation in the estimates of these parameters on the separate
data sets (data on file), the combined day 1 and repeat dose data were used in subsequent
analyses.
Model diagnostics based on the distribution of various types of residuals (Figure D.6) and
QQplots (Figure D.7) suggest no systematic deviations (i.e residuals evenly scattered ).
The residuals are PWRES (population weight residuals), IWRES (Individual weighted
residuals) and NPDE (normalised prediction distribution error) and corresponding
probability distribution function and QQplots. No marked bias in the distribution of the
structural parameters when plotted versus their respective random effects (Figure D.11).
Table D6
Parameters
Values
Rm (L)
14.7
Baseline effect on Rm
0.414
Tz (h)
0.0407
Tzl (h)
2.41
Ramp
0.0326
Ramp1
0.0139
Kout (l/h)
16.1
15.9
EDK50 (g)
Kde (l/h)
0.0269
Emax (L)
0.275
Value (CV%)
Inter-patient variability ()
0.102 (32%)
Rm
8.99 (300%)
Tz
0.339 (58%)
Tzl
0.392 (63%)
Ramp
0.736 (86%)
Ramp1
0.149
(39%)
Kout
2.99 (173%)
EDK50
1.38 (117)
kde
Residual Error (additive)
Value (CV%)
0.131
R.S.E (%)
2
2
39
1
2
3
1
13
6
6
R.S.E (%)
4
1
3
3
3
3
3
3
r.s.e (%)
1
Visual examination of the post-hoc parameter estimates of each of the model parameters
against the covariates showed correlation of age, gender and baseline with the Rm
parameter. However, after inclusion of the baseline covariate on Rm, the correlation of
age and gender on Rm was redundant. There was no obvious trend in the random
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residuals (etas) with the remaining covariates including weight, height, body mass index,
center and race. The K-PD model adequacy to predict the individual time course of
FEV1was also demonstrated for all the individual patients after single or repeat dose.
Some examples of the individual versus observed time course of FEV1 are depicted in
Figure D.8, Figure D.9 and Figure D.10.
The predicted population Emax of 0.275L (95%CI: 0.245-0.305L) is consistent with the
statistical output for repeated measures mixed effects analysis of serial FEV1. The
maximum LSMean FEV1 difference from placebo was 0.278L (95%CI: 0.192-0.365L) on
day 1 and 0.240L (95%CI: 0.146-0.333L) at the top dose of 50 g od.
Besides the estimation of diurnal baseline parameters for characterising the placebo time
course of FEV1, some key drug-related parameter estimates need to be put into context.
The EDK50 of 15 g/h is an apparent potency as it relates to the dose rate that achieves
50% of predicted maximum FEV1 response. This dose rate is the product of the
estimated amount of drug in the lung biophase at any time post dose and the estimated
geometric mean elimination half life of the drug (KDE: 26h (95%CI: 23-29h)) from the
lung. The KDE parameter estimated is a rate constant that expresses the equilibrium
between the amount of GW642444 in the lung biophase with time and its product with
dose (KDE * A(t)) drives the pharmacodynamic response in the lung biophase. It is
therefore expected that the duration of FEV1 response be dose-dependent.
Estimation of duration of effect parameter (Dur 150mL) using the observed time course
of FEV1(change from baseline) confirms the dose-dependent duration of FEV1 response
(Table D7). At the threshold clinical response of 150mL, there is a dose-dependent
increasing trend in the duration of FEV1 response (Dur 150mL) with increase in dose.
The 6.25, 12.5, 25 g and 50 g dose schedule provides a median Dur 150mL of 20h
compared to the lowest dose of 3 g that provides a Dur 150mL of about 14h. These
data also confirm the intrinsic long duration of activity of GW642444.
Table D7
Dose (g)
0
86
3
83
6.25
90
12.5
88
25
89
50
98
Source data : Table 9.9
95th CI Median
5th
4.2
10.9
18.2
17.1
20.6
20.2
6.9
13.6
20.9
19.5
23
22.6
95th
9.6
16.3
23.6
22.0
25.4
25.0
Discussion
The K-PD approach allows the analysis of the kinetic of drug action in the absence of
pharmacokinetic data. This method can be applied optimally provided certain design
aspects are taken into account. These include adequate number of patients, a wide range
of doses, different dose regimens (e.g. single and repeat dose) and adequate
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pharmacodynamic measurements covering the dosing time interval. The present study
provides the necessary data to adequately apply the K-PD methodology. This is evident
from the reasonable precision (mostly below 30%) of the parameter estimates obtained
from the K-PD analysis.
A key aspect of this analysis was to adequately describe the diurnal variation of the
baseline (placebo) FEV1 response in the present study to be able to reliably predict the
time course of FEV1 due to GW642444 alone. The dual cosine function was optimal in
describing the pulmonary circadian profile in asthmatics. Further confirmation of this
model for placebo profile in studies where GW642444M is given in the morning or
evening is required. Examination of individual as well as LSMean time course of FEV1
(absolute and change from baseline) by dose and regimen suggests good concordance
with the observed and model fitted time course of FEV1 over the dose range of 0-50ug
after single and repeat od dosing at steady state.
The model-based analysis of the FEV1 response data in the present study has provided
additional insight on the trough dose response of GW642444M in terms of characterising
the potency and maximum predicted FEV1 effect. A key advantage of using all
individual response data for dose-response modelling ensures robust estimation of the
dose-response model parameters as well as the associated uncertainty distribution of
these parameters. Simulation of the likely dose-response distributions using the model
parameters and associated uncertainty showed that 12.5 g GW642444 and above can
achieve a target FEV1 response (change from baseline) of 100mL in at least half the
number of patients at trough. This is also reflected in the estimation of duration of
response (DUR150mL) parameter from the observed time course of FEV1 data. As
expected, there was an incremental increase in the DUR150mL parameter with dose,
with the 6.25 g to 50 g OD showing a sustained duration of effect of 20 h at steady
state and is consistent with the estimated long elimination half life of the drug in the lung
biophase.
Conclusions
Age, baseline FEV1 and gender were significant covariates accounting for variability
in the placebo response.
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From the K-PD model, an elimination half life of 26 h (95%CI: 23-30h) of the drug
in the lung biophase in equilibrium with lung FEV1 response would be consistent
with the sustained duration of FEV1 response over 24 h dosing interval at all doses.
Using a clinical threshold of 100 mL FEV1 over the entire time course of FEV1
profile confirms the dose-dependent duration of FEV1 response. The 6.25 to 50 g
dose schedule provides a median duration 100 mL of 20 h compared to the 3 g
dose that provides a duration 100mL of about 14 h. This is consistent with the peak
to trough ratio of unity across all doses.
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Figure D.6
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Figure D.7
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Figure D.8
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Figure D.9
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This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
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Figure D.10
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This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
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Figure D.11
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This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available subject
to an approved research proposal. For further information please see the Patient Level Data section of
the GSK Clincal Study Register.
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References
1.
2.
3.
Delyon B & Lavielle M (1999) Computational Statistics and Data Analysis, 27:94128
4.
5.
6.
7.
8.
9.
Mentre F & Escolano S (2005): Prediction of discrepancies for the evaluation of non
linear mixed effects models, J Pharmacokinetics & Pharmacodynamics , 33, 3, 345367
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This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
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Synopsis
Identifier: YM2008/00019/00 Study Number: B2C109575
Title: A randomised, double-blind, placebo-controlled, parallel group, dose ranging
study evaluating the efficacy and safety of GW642444M administered once daily
compared with placebo for 28 days in adolescent and adult subjects with persistent
asthma.
Investigator(s): 88 Investigators screened subjects (84 Investigators with ITT subjects).
Study centre(s): Multi-centre study
Publication(s): None at the time of this report
Study Period: 29 Dec 2007 (FSFV) 10 Sept 2008 (LSLV)
Phase of Development: IIb
Objectives: The primary objective of this study was to evaluate the dose response,
efficacy and safety of five doses of GW642444M (3 g, 6.25 g, 12.5 g, 25 g and 50
g) over a 28-day treatment period in adolescent and adult subjects with persistent
asthma. The secondary objective was to characterise the population pharmacokinetics
(PK) of GW642444M in these subjects.
Methodology: This was a multi-centre, randomised, placebo-controlled, double-blind,
parallel group study. Subjects were screened at Visit 1, and those who met eligibility
criteria completed a 14-day pre-treatment Run-in period. At Visit 2, subjects were
stratified in an approximately 1:1 ratio according to their baseline forced expiratory
volume in one second (FEV1) as a percentage of predicted normal, with one stratum for
those with FEV1 percent predicted 40% - 65% and one for those with FEV1 percent
predicted > 65% - 90%. Subjects were then randomised to one of six treatments for 28
days: GW642444M 3 g, 6.25 g, 12.5 g, 25 g, 50 g, or placebo, administered via
the Novel Dry Powder Inhaler once-daily in the evening. At the end of the treatment
period, subjects entered a seven-day Follow-up period. Throughout the study (from
Screening to Follow-up), subjects remained on their current inhaled corticosteroid
therapy (ICS) at fixed doses. The overall study duration (Screening to Follow-up) for
each subject was 7 weeks.
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Number of subjects:
GW642444M
placebo
Total
3 g
6.25 g 12.5 g 25 g
50 g
Number of subjects planneda, N
99
99
99
99
99
99
594
Randomised, N
103
102
102
102
103
102
614
Completed, n (%)
86 (84)
84 (83) 91 (90)
88 (88) 93 (92) 97 (95) 539 (89)
Total nr subjects withdrawn, n (%)
16 (16)
17 (17) 10 (10)
12 (12)
8 (8)
5 (5)
68 (11)
Withdrawn due to AEs, n (%)
0
1 (<1)
0
0
1 (<1)
0
2 (<1)
Withdrawn due to lack of efficacy, n (%)
9 (9)
12 (12)
3 (3)
5 (5)
4 (4)
0
33 (5)
Withdrawn for other reasons, n (%)
7 (7)
4 (4)
7 (7)
7 (7)
3 (3)
5 (5)
33 (5)
a. 1140 subjects were screened with the aim of achieving 594 evaluable subjects (99 subjects per group).
Seven subjects were randomised in error but did not receive study drug. One subject was not randomised but took the
study drug in error. AE: Adverse event.
Diagnosis and main criteria for inclusion: Male and female subjects of 12 years of
age with persistent asthma. In Germany, the Russian Federation and South Africa, which
permitted enrolment of adults only, subjects were 18 years of age. In Chile one centre
was allowed to only recruit subjects >15 years of age and the other centre >18 years of
age.
Treatment administration: Subjects who at Visit 2 were randomised to one of the
double-blind 28-day treatments were instructed to administer one inhalation of study
medication using the Novel Dry Powder Inhaler once-daily in the evening following predose symptom assessment. The first dose of study medication was given on treatment
Day 1 during clinic Visit 2. On days 7, 14 and 28 (Visits 3, 4 and 5, respectively),
subjects were required to take their dose of study medication at the clinic. On other
treatment days, subjects administered their study medication at home.
Criteria for evaluation: The primary efficacy endpoint was the mean change from
baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the
28-day treatment period. The trough FEV1 was defined as the mean of the FEV1 values
obtained 23 and 24 hours (h) after dosing on Day 28.
Secondary efficacy endpoints:
Change from baseline in weighted mean 24 h serial FEV1 on Days 1 and 28 (mean
post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24
h). This endpoint was derived for all subjects but the 6 and 12 h time points were
only measured in a sub-group of subjects (66% of subjects).
Mean change from baseline in daily morning PEF averaged over the 28-day
treatment period.
Mean change from baseline in the percentage of symptom-free 24-h periods during
the 28-day treatment period.
Mean change from baseline in the percentage of rescue-free 24-h periods during the
28-day treatment period.
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Proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
(0-4 h) on Days 1 and 28. An additional post-hoc analysis of Proportion of subjects
obtaining 200 mL and 12% increase from baseline in FEV1 (0-24 h) on Days 1
and 28 was performed.
Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24 h,
7 and 14 days of treatment).
Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.
Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.
Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.
Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.
Mean change from baseline in daily morning PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.
Mean change from baseline in daily evening PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.
Weighted mean change from baseline (0-4 h) for FEV1 on Days 1 and 28.
Proportion of subjects obtaining a greater or equal than 15% increase from baseline
in FEV1 (0-4 h) on Days 1 and 28.
Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 was defined as the
mean of the FEV1 values obtained 23 and 24 hours (h) after dosing on Day 28, with
no imputation.
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Safety endpoints:
Safety endpoints included adverse event (AE) reporting throughout the 28-day treatment
period; haematological and clinical chemistry parameters after 14 days and 28 days of
treatment and dipstick urinalysis parameters after 28 days of treatment; vital signs (pulse
rate and systolic and diastolic blood pressure) on Days 1, 7, 14 and 28; 12-lead
electrocardiogram (ECG) on Days 1, 7, 14 and 28; and fasting potassium and glucose on
Days 1 and 28 and non-fasting potassium only on Days 7 and 14.
Pharmacokinetic endpoints:
Plasma concentrations of GW642444, the triphenylacetate counterion and the GW642444
metabolites GW630200 and GSK932009, and derived PK parameters for GW642444 in
subjects with persistent asthma following once-daily treatment for 28 days. Relationship
between systemic exposure to GW642444 (Cmax) and systemic pharmacodynamic
endpoints.
Statistical methods:
In total, 1140 subjects were screened with the aim of achieving 594 evaluable subjects
(with at least one pre-dose or 23-24 h post-dose FEV1 assessment on or after nominal
Day 7) or 99 subjects per group. This sample size was based on the primary endpoint of
change from baseline in trough FEV1 and was powered at 97% to detect a dose response
effect of 200 mL improvement per 50g of GW642444M. This assumed a standard
deviation of 430mL and significance declared at the two-sided 5% level. The primary
treatment comparison was a test of linear trend in dose response in trough (prebronchodilator and pre-dose) evening FEV1 derived from the mean of the 23 and 24 h
post-dose assessments at Day 28 across the five doses of GW642444M relative to
placebo to demonstrate overall efficacy of GW642444M. If this test was statistically
significant, two-sided pair-wise tests of each dose versus placebo were performed to
demonstrate superiority of individual doses over placebo. Pair-wise comparisons of each
dose versus placebo were also performed for the other key efficacy endpoints. The
primary analysis was performed using Analysis of Covariance (ANCOVA) with effects
due to baseline FEV1, centre grouping (country), age, sex, baseline percent predicted
FEV1 stratum and dose/treatment group, imputing missing data using last observation
carried forward (LOCF). For this analysis the Intent-To-Treat (ITT) Population was
used, which was the primary population for all analyses of efficacy and safety measures
comprising all subjects randomised to treatment and who received at least one dose of
trial medication. The primary comparisons were supported by the same tests performed
using the Per Protocol (PP) Population, which consisted of all subjects in the ITT
Population who did not have any full protocol deviations which were related to the
efficacy endpoints. They were also supported by the same tests performed using a
repeated measures mixed model on the ITT Population. The dose response across the
five doses of GW642444M was explored using the ITT Population excluding placebo
from the analysis. Plasma concentrations of GW642444, the triphenylacetate counterion
and the GW642444 metabolites GW630200 and GSK932009 from the PK concentration
population (ITT population for whom a PK sample was obtained and analysed) were
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summarised descriptively. Supporting analyses were performed to characterise the doseresponse parameters and a model framework for the time course of FEV1.
Summary:
Efficacy: The primary analysis, the test of linear trend in dose response in trough
evening FEV1 at Day 28 versus placebo, showed a statistically significant result, thus
allowing further pair-wise comparisons across the treatment groups. Statistically
significant dose-dependent improvements in trough FEV1 compared with placebo were
found for the 12.5 g, 25 g and 50 g GW642444M doses, with mean treatment
differences compared with placebo of 130 mL, 121 mL and 162 mL, respectively, despite
a placebo effect of 147 mL versus baseline. The superiority of these three highest
GW642444M doses relative to placebo was confirmed by Per Protocol analysis and
repeated measures analysis of the primary endpoint. A similar dose-response was found
for both FEV1 percent predicted strata, indicating that the dose-response relationship was
similar for the two disease severities.
Secondary and other efficacy measures supported the findings of the primary efficacy
endpoint by demonstrating a dose response across the doses studied. Serial FEV1
measurements taken on Days 1 and 28 showed that all GW642444M treatment groups
had statistically significantly greater improvements versus placebo in weighted mean
change from baseline FEV1 (0-24 h) except for 6.25 g dose on Day 1. The greatest
improvements in weighted mean change from baseline FEV1 (0-24 h) were seen in the 25
g and 50 g GW642444M groups (193 mL 215 mL on Day 1, and 165 mL - 172 mL
on Day 28). Dose dependent improvements were seen in the proportion of subjects
achieving 200 mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h
maximum and peak FEV1 , as well as morning and evening PEF the percentage of
symptom-free 24-h periods and rescue-free 24-h periods with the greatest improvements
observed in the 25 g and 50 g groups.
Evidence of sustained bronchodilation with GW642444M was supported by repeated
measures analysis of trough FEV1, serial FEV1, ratio of peak post FEV1 to trough FEV1
and PM PEF assessments. Repeated measures analysis of trough FEV1 showed a dosedependent response with statistically significant improvements in trough FEV1 at 23-24 h
post dose on Day 28 for 12.5 g, 25 g GW642444M compared with placebo; as well as
50 g GW642444M at pre-dose on Day 7, Day 14 and Day 28, and at 23-24-h post-dose
on Day 28. Serial FEV1 profiles both on Day 1 and Day 28 demonstrated
bronchodilation over 24-hours for all GW642444M treatments. The ratio of peak postdose FEV1 to trough FEV1 across all the GW642444M doses was close to 1, suggesting
that the 24-h duration of action is an intrinsic property of the molecule and not a function
of dose. PM PEF, measured pre-evening dose, also showed bronchodilation out to 24hours with increases of >30 L/min in the 25 g and 50 g groups.
A numerically higher percentage of subjects were withdrawn due to lack of efficacy from
the placebo and 3 g GW642444M group (9 and 12% of subjects, respectively)
compared with the 6.25 g, 12.5 g and 25 g treatment groups (5%). No withdrawals
were reported for the 50 g GW642444M group. There was no statistically significant
difference between any of the GW642444M doses and placebo with regards to the
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Conclusions:
The Per Protocol and repeated measures analyses confirmed the results from the
primary analysis by demonstrating the superiority of 12.5 g, 25 g and 50 g doses
GW642444M relative to placebo.
Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, treatment with 25
g and 50 g GW642444M resulted in consistently greater improvements in lung
function (weighted mean 24-h serial FEV1, proportion of subjects achieving 200
mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h maximum and
peak FEV1), morning and evening PEF as well as symptoms and rescue use
(percentage of symptom- and rescue free 24-h periods).
A greater withdrawal rate due to lack of efficacy with the lower doses compared to
the higher GW642444M doses are consistent with the findings of the primary and
other efficacy analyses.
Broadly similar dose response effects were found for the lower and upper strata,
suggesting that different doses of GW642444M may not be required for different
severities of asthma.
There were no clinically relevant increases from baseline versus placebo in serial,
weighted mean or maximum QTc(F) (0-4 h) for any treatment group, at any time
point. Although increases in mean serial QTc(B) from baseline versus placebo of 6
msec to 12.5 msec in the 25 g and 50 g GW642444M groups were above the 5
msec threshold of clinical concern, QTc(F) was acknowledged as the more robust
correction for drugs that are associated with increased heart rate, with QTc(B) being a
poorer correction factor.
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Potassium and glucose values did not exceed the predefined levels of clinically
relevant concern. No AEs of hypokalaemia were reported.
PK analysis showed that GW642444 shows a good therapeutic margin over the dose
range studied. There were limited measurable drug levels above the quantification
limit of 30 pg/mL up to 25 g dose, without a clear relationship between systemic
exposure (observed Cmax over period 2-30 min post-dose) and any systemic PD
endpoint (pulse rate, QTc, glucose or potassium).
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Title:
21-APR-2004
GM2006/00690/03
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The GlaxoSmithKline group of companies
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Revision Chronology:
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2007-NOV-01
Original
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2007-DEC-17
GM2006/00690/02
2008-APR-09
Amendment No.2:
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2008-APR-21
Amendment 3:
To amend an error to text in
randomisation criterion 7.
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GlaxoSmithKline
Ironbridge Road
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
Telephone:
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
Sponsor Contact Information:
Sponsor Serious Adverse Events (SAE) Contact Information:
Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP)
Greenford, UK
Email:
Fax:
United States Medical Monitor:
MD (Director, Respiratory Medicine Development Centre)
Tel:
Mobile:
European and International Medical Monitor:
MA, BM BCh, MFPM (Director, Respiratory Medicine Development
Centre)
Tel:
Mobile:
Regulatory Agency Identifying Number(s):Eudract No. 2007-001713-42
IND No. 74,696
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Investigator Signature
Date
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TABLE OF CONTENTS
Page
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Discussion of Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. STUDY TREATMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Investigational Product and Reference Therapy . . . . . . . . . . . . . . . .
5.2. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Product Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Concomitant Medications and Non-Drug Therapies . . . . . . . . . . . . .
5.6.1. Permitted Medications and Non-Drug Therapies . . . . . . . . . . .
5.6.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . .
5.7. Treatment after the End of the Study . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . .
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7. DATA MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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11. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1. Appendix 1: PGx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2. Appendix 2: Laboratory Parameters . . . . . . . . . . . . . . . . . . . . . . . .
11.3. Appendix 3: Country Specific Requirements . . . . . . . . . . . . . . . . . .
11.4. Appendix 4: Protocol Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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ABBREVIATIONS
ABV
AE
ALT
AM
ANCOVA
AST
AUC
AV
CFC
CI
COPD
CPK
CRF
DPI
ECG
EDTA
FEV1
GCSP
GINA
GSK
HFA
IB
IEC
ICS
IRB
ITT
IUD
LABA
LDH
LLQ
LOCF
MAO
mcg
MDI
MedDRA
MSDS
NIH
PD
PEF
PGx
PK
PM
PP
QTc(b)
RAMOS
RAP
Absolute By Volume
Adverse Event
Alanine aminotransferase
Morning
Analysis of Covariance
Aspartate Aminotransferase
Area Under the Curve
Atrioventricular
Chlorofluorocarbon
Confidence Interval
Chronic Obstructive Pulmonary Disease
Creatine Phosphokinase
Case Report Form
Dry Powder Inhaler
Electrocardiogram
Ethylenediaminetetraacetic Acid
Forced Expiratory Volume in 1 second
Global Clinical Safety and Pharmacovigilance
Global Initiative for Asthma
GlaxoSmithKline
Hydrofluoroalkane
Investigator Brochure
Independent Ethics Committee
Inhaled Corticosteroid
Institutional Review Board
Intent To Treat
Intrauterine Device
Long Acting Beta Agonist
Lactate Dehydrogenase
Lower Limit of Quantification
Last Observation Carried Forward
Monoamine Oxidase
Microgram
Metered Dose Inhaler
Medical Dictionary for regulatory Activities
Material Safety Data Sheet
National Institutes of Health
Pharmacodynamics
Peak Expiratory Flow
Pharmacogenetics
Pharmacokinetic
Evening
Per Protocol
QTc corrected for Bazetts formula
Registration and Medication Ordering System
Reporting and Analysis Plan
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SPM
ULN
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Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
DISKUS
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PROTOCOL SUMMARY
Rationale
Clinical rationale: The purpose of this study is to evaluate the efficacy and safety of five
doses of GW642444M administered once-daily compared with placebo in subjects with
persistent asthma over a 28-day period. The information obtained will be used to select
the optimum dose for further studies.
Pharmacokinetics Rationale: Pharmacokinetic samples from randomised subjects will be
collected using a population pharmacokinetics (PK) approach. In contrast to traditional
pharmacokinetic methods, the population PK approach allows the identification and
measurement of pharmacokinetic variability in subjects representative of the target
population and the explanation of that variability by identifying factors that may
influence the pharmacokinetic behaviour of the drug. This approach also allows
estimation of the unexplained (random) variability in the patient population, which is
important, since an increase in random variability may result in an underestimate of
efficacy and/or safety. Defining the optimum dose for later stages of development can be
made more efficient by understanding the variability in the pharmacokinetics of a drug.
Objective(s)
Primary Objective
To evaluate the dose response, efficacy and safety of five doses of GW642444M (3mcg,
6.25 mcg, 12.5 mcg, 25mcg and 50 mcg) over a 28 day treatment period in subjects with
persistent asthma
Secondary Objective
To characterise the population pharmacokinetics of GW642444 in subjects with
persistent asthma
Study Design
This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group
study. Subjects will enter a two week run-in period and those who then fail to meet
eligibility criteria for randomisation will be withdrawn from the study. Those subjects
who meet the eligibility criteria at the end of the run-in period will be stratified in an
approximately 1:1 ratio according to their baseline FEV1 as a percentage of predicted
normal - one stratum for those with FEV1 percent predicted 40% - 65% and one for
those with FEV1 percent predicted > 65%-90%. Once stratified, subjects will be
randomised to one of the following treatments and enter into a 28 day double-blind
treatment period (-4/+2days):
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There will be a 7 day follow-up period following the end of the treatment period.
Subjects will remain on their current inhaled corticosteroid therapy (at fixed doses)
throughout the study (screening to follow-up inclusive). At the end of the follow-up
period, subjects will be prescribed appropriate alternative asthma therapy, if required. A
subject will be regarded as having completed the study if they complete all phases of the
study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.
Study Endpoints/Assessments
Primary Endpoint
Mean change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1
at the end of the 28-day treatment period. The trough FEV1 will be defined as the mean of
the FEV1 values obtained 23 and 24 hours after dosing on Day 28.
All other endpoints will be derived from the following assessments:
12-lead ECGs
Clinical laboratory safety tests (including additional potassium and glucose profiling)
Adverse events
Pharmacokinetic sampling
Pharmacogenetic sampling
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1.
INTRODUCTION
1.1.
Background
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1.2.
Rationale
Clinical rationale: The purpose of this study is to evaluate the efficacy and safety of five
doses of GW642444M administered once-daily compared with placebo in subjects with
persistent asthma over a 28-day period. The information obtained will be used to select
the optimum dose for further studies.
Pharmacokinetics Rationale: Pharmacokinetic samples from randomised subjects will be
collected using a population pharmacokinetics (PK) approach. In contrast to traditional
pharmacokinetic methods, the population PK approach allows the identification and
measurement of pharmacokinetic variability in subjects representative of the target
population and the explanation of that variability by identifying factors that may
influence the pharmacokinetic behaviour of the drug. This approach also allows
estimation of the unexplained (random) variability in the patient population, which is
important, since an increase in random variability may result in an underestimate of
efficacy and/or safety. Defining the optimum dose for later stages of development can be
made more efficient by understanding the variability in the pharmacokinetics of a drug.
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2.
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OBJECTIVE(S)
Primary Objective
To evaluate the dose response, efficacy and safety of five doses of GW642444M (3mcg,
6.25mcg, 12.5mcg, 25mcg and 50mcg) over a 28 day treatment period in subjects with
persistent asthma
Secondary Objective
To characterise the population pharmacokinetics of GW642444 in subjects with
persistent asthma
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
There will be a 7 day follow-up period following the end of the treatment period.
Subjects will remain on their current inhaled corticosteroid therapy (at fixed doses)
throughout the study (screening to follow-up inclusive). At the end of the follow-up
period, subjects will be prescribed appropriate alternative asthma therapy, if required. A
subject will be regarded as having completed the study if they complete all phases of the
study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.
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The schematic below illustrates the clinic visits required for each phase of the study.
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3.2.
Discussion of Design
Five doses of GW642444M (3mcg, 6.25mcg, 12.5mcg, 25mcg and 50mcg) have been
selected for this phase IIb dose ranging study. The doses have been selected based upon
results from 2 Phase I studies (B2C10001 and B2C108784 [GlaxoSmithKline Document
Number SM2003/00028/05]) and 4 Phase IIa studies (B2C101762, B2C104604,
B2C106093 [GlaxoSmithKline Document Number SM2003/00028/05], and B2C106996
[GlaxoSmithKline Document Number RM2007/00094/00]). The 3mcg dose has been
included as a potential no-effect dose. The 50mcg dose is included as a likely supratherapeutic dose to help establish the therapeutic index for GW642444M and to assess
whether or not a plateau has been achieved. The intervening doses of 6.25mcg, 12.5mcg
and 25mcg represent doubling-dose increments between the lowest and highest doses.
By evaluating a range of doses from 3mcg to 50mcg of GW642444M, it will be possible
to assess the dose response of GW642444M as well as the potential effects of
GW642444M on typical pharmacological class effects (e.g., increased heart rate,
decreased potassium levels, increased glucose levels). The data will provide useful
information in determining the therapeutic index of GW642444M and in selecting the
dose(s) of GW642444M to be carried forward in the Phase III program in the
GW685698X/GW642444M combination product.
The studies performed to date have been conducted with morning dosing. For Phase IIb,
the intention is to dose in the evening to match the corticosteroid dose ranging studies.
However, GSK intends to also explore morning dosing with GW642444 as part of the
ICS/LABA combination development program. Based on observations with salmeterol,
GSK does not expect the efficacy or safety profile to differ based on dosing in the
evening [GlaxoSmithKline Document Number RM2003/00283/00].
Treatment duration of 28 days is considered to be sufficient to demonstrate that the
efficacy of GW642444M is maintained without tolerance
4.
4.1.
Number of Subjects
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4.2.
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Inclusion Criteria
Complete abstinence from intercourse from screening until 2 weeks after the
follow-up contact; or
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Estrogenic vaginal ring inserted for at least 1 month prior to study medication
administration; or
Asthma Therapy
fluticasone propionate MDI CFC/HFA
fluticasone propionate DPI
beclomethasone dipropionate
beclomethasone dipropionate HFA (Qvar)
budesonide DPI/MDI
Flunisolide
triamcinolone acetonide
mometasone furoate
Ciclesonide
CFC=chlorofluorocarbon HFA=hydrofluoroalkane
1. Ex-actuator dose
2. Ex-valve dose
In France, a subject will be eligible for inclusion in this study only if either affiliated
to or a beneficiary of a social security category.
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4.3.
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Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study:
1
Participated in any study using an investigational drug during the previous 30 days or
will participate simultaneously in another clinical trial.
A subject must not have any clinically significant, uncontrolled condition or disease
state that, in the opinion of the investigator, would put the subject's safety at risk
through study participation or would confound the interpretation of the efficacy
results if the condition/disease exacerbated during the study.
The list of additional excluded conditions/diseases includes, but is not limited to the
following:
2 or more measurements with systolic blood pressure 160mmHg or diastolic blood pressure
100mmHg[NIH, 2004]
history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission =
no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an
approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be
enrolled [American Thoracic Society Documents, 2005; American Thoracic Society, 2003]
Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic
fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.
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Any adverse reaction including immediate or delayed hypersensitivity to any 2agonist or sympathomimetic drug, or known (i.e., patients with a history of severe
milk protein allergy) or suspected sensitivity to the constituents of GW642444M
inhalation powder (e.g., lactose or magnesium stearate).
Subjects who are likely to be non-compliant with study medication and other studyrelated requirements (e.g. attendance at clinic visits or completion of Daily Diary).
Theophyllines
Slow-release bronchodilators
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4.4.
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Randomisation Criteria
At the end of the run-in period subjects must fulfil the following additional criteria in
order to enter the treatment period of the study:
1.
Best baseline pre-dose FEV1 at Visit 2 40% and 90% of their predicted normal.
2.
3.
4.
5.
Ventricular rate < 45 beats per minute or > 90 beats per minute
Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.
6.
7.
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expected to affect the subjects asthma status or the subjects ability to participate in
the study.
8.
9.
10. Compliance with completion of the Daily Diary. Non-compliance with completion
of the Daily Diary, defined as:
Completion of AM and PM symptom scores on less than 4 days out of the last 7
days immediately preceding Visit 2.
Completion of AM and PM rescue use on less than 4 days out of the last 7 days
immediately preceding Visit 2.
4.5.
Withdrawal Criteria
A subject will be regarded as having completed the study if they complete all phases of
the study (screening, treatment period and follow-up).
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is
considered to be detrimental for them to continue in the study. Reasons for withdrawal
can include: an adverse event, lost to follow-up, protocol violation, lack of efficacy,
sponsor terminated study, non-compliance, pregnancy, abnormal liver function test,
abnormal laboratory results, or for any other reason. Subjects are also free to withdraw
themselves from the study at anytime, although every effort should be made to persuade
them to return to the clinic for an early withdrawal visit and to return all study related
materials.
Subjects should be withdrawn from the investigational product for any of the following
reasons. Once withdrawn from the investigational product a subject will be considered
withdrawn from the study.
A subject experiences any of the following abnormalities in ECGs. (the decision should
be made following consultation with the medical monitor, unless there is an immediate
safety concern and this is not feasible).
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Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.
Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.
Clinic FEV1 below the FEV1 Stability Limit value calculated at Visit 2 pre-dose
FEV1 at Visit 2 x 80%).
During the 7 days immediately preceding the visit, the subject experienced any
of the following:
> 3 days in which PEF has fallen below the AM PEF Stability Limit calculated
at Visit 2 (Mean AM PEF from the 7 days preceding Visit 2 x 80%)
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When subjects meet the following liver chemistry threshold criteria, investigational
product must be permanently withdrawn, additional testing performed, and the subject
monitored until liver chemistries resolve, stabilize, or return to baseline values. The
subject must then be permanently withdrawn from the study (see Section 6.3.3 for further
details).
ALT 5xULN.
At withdrawal, study related equipment should be returned by the subject and if possible
an Early Withdrawal Visit (See Table 1) should be conducted within 24 hours of the
subjects stopping study medication. In the event a subject withdraws at, or during, a
scheduled visit, an Early Withdrawal Visit is not required. However, all study procedures
scheduled at an Early Withdrawal Visit must be performed at this visit instead. A followup visit should be made 7 days (-4/+2days) after the Early Withdrawal Visit.
Subjects who are withdrawn from the study will not be replaced. The primary reason for
withdrawal will be recorded in the CRF and any data collected up until the point of
withdrawal will be used in the analyses.
5.
STUDY TREATMENTS
5.1.
Compound
Formulation
Dosage Form
Unit Dose Strength(s)
Route of Administration
GW642444M
First strip: GW642444X micronised
drug (as the M salt
triphenylacetate) blended with
lactose and magnesium stearate
Second strip: placebo containing
lactose
Novel dry powder inhaler 30 doses
per device
3 mcg per blister
6.25 mcg per blister
12.5 mcg per blister
25 mcg per blister
50mcg per blister
Inhaled
Placebo
First strip: blend of lactose
and magnesium stearate
Second strip: lactose
Inhaled
Salbutamol/albuterol MDI for use as rescue medication throughout the study will be
sourced locally or by GSK for sites in the United States of America, for all other sites it
will be sourced locally where possible.
The contents of the label will be in accordance with all applicable regulatory
requirements.
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GW642444M 3mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening
GW642444M 6.25mcg (1 actuation) administered once daily via the novel dry
powder inhaler in the evening
GW642444M 12.5mcg (1 actuation) administered once daily via the novel dry
powder inhaler in the evening
GW642444M 25mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening
GW642444M 50mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening
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Placebo (1 actuation) administered once daily via the novel dry powder inhaler in the
evening
The duration of treatment for each subject is 28 days. On Days 1 and 2 (Visit 2/2a), Day
7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5) subjects will be required to take their
dose of study medication at the clinic. Study medication will be given at the clinic at
approximately the same time of day ( 1 hour) as Day 1 (Visit 2). On other days, subjects
will be instructed to take their study medication within 1 hour of their dose time on Day
1 (Visit 2). Doses should be taken prior to usage of rescue salbutamol/albuterol. Subjects
will be required to fast for at least 4 hours prior to the planned pre-dose blood sample
until after the 4 hours post-dose assessments on Days 1 and 28 (Visits 2 and 5
respectively)
Inhaled salbutamol/albuterol will be provided for symptomatic relief during the run-in
treatment period and follow-up period.
5.2.
Treatment Assignment
5.3.
Blinding
This is a double-blind study. Neither the subject nor the Investigator will know which
study medication the subject is receiving. Placebo dry powder formulations will be
provided which are indistinguishable from GW642444M formulation.
The investigator or treating physician may unblind a subjects treatment assignment only
in the case of an emergency, when knowledge of the study treatment is essential for the
appropriate clinical management or welfare of the subject. Whenever possible, the
investigator must first discuss options with the GSK Medical Monitor or appropriate
GSK study personnel before unblinding the subjects treatment assignment. If this is
impractical, the investigator must notify GSK as soon as possible, but without revealing
the treatment assignment of the unblinded subject, unless that information is important
for the safety of subjects currently in the study. The date and reason for the unblinding
must be recorded in the appropriate data collection tool.
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GSKs GCSP staff may unblind the treatment assignment for any subject with an SAE. If
the SAE requires that an expedited regulatory report be sent to one or more regulatory
agencies, a copy of the report, identifying the subjects treatment assignment, may be sent
to clinical investigators in accordance with local regulations and/or GSK policy.
Subjects should be withdrawn from the study if their treatment code becomes unblinded.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of GSK
investigational product dispensed and/or administered to study subjects, the amount
returned by study subjects, and the amount received from and returned to GSK, when
applicable. Product accountability records must be maintained throughout the course of
the study.
5.5.
Treatment Compliance
5.6.
5.6.1.
All concomitant medications taken during the study will be recorded in the CRF. The
minimum requirement is that drug name and the dates of administration are to be
recorded.
The following asthma medications are permitted:
Inhaled corticosteroids are permitted during the study provided the dose remains
constant for at least 4 weeks prior to Visit 1 and remains constant throughout the
study period. The maximum allowable inhaled corticosteroid doses are as follows:
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Asthma Therapy
fluticasone propionate MDI CFC/HFA
fluticasone propionate DPI
beclomethasone dipropionate
beclomethasone dipropionate HFA (Qvar)
budesonide DPI/MDI
flunisolide
triamcinolone acetonide
mometasone furoate
Ciclesonide
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Ex-actuator dose
Ex-valve dose
All medications for other disorders (other than those listed in Section 5.6.2) may be
continued throughout the study (including those to treat attention deficit hyperactivity
disorder), provided the dose remains constant and their use would not be expected to
affect the subject's lung function.
Intranasal corticosteroids, intranasal sodium cromoglicate, and topical corticosteroids are
permitted if started prior to Visit 1 and kept at a stable dose throughout the study.
Immunotherapy for treatment of allergies is permitted if started prior to Visit 1 and
remains at a stable dose throughout the study. Hormonal replacement therapy for the
treatment of menopausal symptoms will be permitted if started prior to Visit 1 and
remains at a stable dose throughout the study.
Short-acting and long-acting antihistamines are allowed to control symptoms of allergic
disorders, however, subjects are permitted to use either one oral or one intranasal
antihistamine during the trial. In addition, antihistamine eye drops are allowed during the
trial.
Non-drug therapies for conditions other than asthma may be used during the study if their
use is not considered likely to have an impact on the subject's asthma.
If a subjects current medication is changed as a result of study participation, then
consent will be obtained at this point and the subject will be required to return to the
clinic to complete the screening visit (Visit 1) once the required wash-out has been
completed.
An example of a change as a result of study participation is if subjects treated with
combination therapy consisting of an inhaled corticosteroid and an inhaled long acting
beta2 agonist are switched to the ICS alone (dose to remain constant) in order to allow the
inhaled ICS to be continued (at a stable daily dose) throughout the study.
5.6.2.
The following medications are not permitted during the conduct of the study or within
the specified time prior to the study. A more comprehensive list of examples for each of
the classes outlined below can be found in the SPM.
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Theophyllines
Slow-release bronchodilators
In addition, a subject may not concurrently use any other prescription or over-the-counter
medication which may affect the course of asthma, or interact with sympathomimetic
amines throughout the study (Visit 1 to Visit 6 inclusive), such as:
Polycyclic antidepressants
Phenothiazines
5.7.
At the end of the follow-up period the investigator should prescribe appropriate
alternative asthma therapy for the subject. There will be no provision to supply
GW642444M after the end of the follow-up period.
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GSK is not recommending specific treatment guidelines for overdose and toxicity
management relating to GW642444M. The investigator is advised to refer to the relevant
document(s) for detailed information regarding warnings, precautions, contraindications,
adverse events, and other significant data pertaining to the study drug being used in this
study. Such documents may include, but not be limited to, the IB or equivalent document
provided by GSK. Clinical judgment should be used in treating the overdose.
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6.
Table 1
Procedures
Visit
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Written Informed
x
Consent
Subject Demography x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination x
Inclusion/Exclusion
x
Criteria
Randomisation
Criteria
Efficacy Assessments
Clinic measured FEV1 x
FEV1 response to
X12
salbutamol/albuterol
x
Issue Diary and PEF
meter9
Review Diary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
x
Serum Pregnancy
Test 13
Urine pregnancy
Test13
HBsAg and hepatitis
x
C antibody
Exploratory Lab Assessments
PK sampling6
Serum potassium
and plasma glucose
sampling
Treatment
2/2A1
1
Early
Withdrawal
3
7 (-4/+2)
4
14(-4/+2)
5/5A1
28(-4/+2)
Follow-up
6
D28 + 7
(-4/+2)
x
x2
x3
x2
x2
x2
x3
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x5
x
x7
x10
x
X11
x
X11
x
x7
Continued
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Table 1
Procedures
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Treatment
Early
Withdrawal
Followup
Investigational product
Dispense Invest.
x
Product.
Assess Invest.
x
x
x
x
Product compliance
Collect invest.
x
x
product
Issue rescue
x
x8
x8
salbutamol/albuterol
Collect used rescue
x
x
x
salbutamol/albuterol
1. Visit 2/2A and Visit 5/5A will take place over 2 days. In selected centres, subjects will be required to remain in the
clinic overnight (~50% of subjects). In other centres, subjects will return to the clinic approximately mid-morning
on Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements
2. On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 to be made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours post-dose. Measurements at 6 and 12 hours post-dose
will only be made in those subjects remaining at the clinic overnight On Days 7 (Visit 3) and 14 (Visit 4) pre-dose
FEV1 measurements required only
3. To be performed 24 hours after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of investigational product
4. Measurements to be made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose,
10minutes and 1, 2 and 4 hours post-dose
5. Samples should be taken pre-dose
6. Samples to be taken as follows:
Day 1 (Visit 2): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
Day 7 (Visit 3): pre-dose
Day 14 (Visit 4): 2minutes -1hour post-dose
Day 28 (Visit 5): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
7. Samples will be taken pre-dose and 10 minutes, 1, 2 and 4hours post-dose. Subject will be fasted from at least 4
hours prior to the pre-dose blood sample until after the 4 hour post-dose sample
8. If required
9. Morning and evening PEF, symptoms and rescue medication usage to be recorded every day from Visit 1 through
Visit 6
10. To be taken 24hours post-dose Day 28
11. Serum potassium only. Samples to be taken pre-dose and 10minutes, 1, 2 and 4 hours post-dose. Subjects are
not required to fast for these samples.
12. Subjects not meeting the FEV1 and/or reversibility inclusion criteria may return to the site once within 4 days to
repeat the lung function tests. The Visit 1 screening period ends and the 14 day Run-in period begins when
subjects meet all of the inclusion criteria
13. Required for all females
Where multiple post-dose assessments are scheduled at the same timepoint the sequence
of assessments should be vital signs, 12-lead ECG, blood sampling and FEV1. FEV1
measurements should be made as close to the scheduled timepoint as possible. A time
deviation window of 15minutes is permitted in the 0 and 2 hour post-dose period. For
assessments scheduled between 2 and 12 hours post-dose a time deviation window of
20 minutes is permitted. For assessments scheduled between 16 and 24 hours a time
deviation window of 30minutes is permitted.
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Smoking history
Reversibility to salbutamol
A subject who has at least one study procedure performed (in addition to signing a
consent form), and is assigned a subject number, but is not randomised is considered a
screen failure.
Subjects who have previously screen failed for any reason prior to Amendment 02 are
allowed to return to the site once to enter the screening process again.
For all subjects (including previous screen failures prior to Amendment 02) not meeting
the FEV1 and/or reversibility inclusion criteria during the Visit 1 screening period may
return to the site once within 4 days to repeat the lung function tests (refer to the SPM for
further details on screen failures).
6.2.
Efficacy
6.2.1.
Efficacy Endpoints
Primary Endpoint
Mean change from baseline in clinic visit trough (pre-bronchodilator and pre-dose)
FEV1 at the end of the 28-day treatment period. The trough FEV1 will be defined as
the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28.
Secondary Endpoints
Change from baseline in weighted mean for 24 hour serial FEV1 on Days 1 and 28
(mean post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23
and 24 hours).
Note: this endpoint will be derived for all subjects but the 6 and 12 hour time points
will only be measured in a sub-group of subjects (approximately 50% of subjects).
Mean change from baseline in daily morning (AM) PEF averaged over the 28-day
treatment period.
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Mean change from baseline in the percentage of rescue-free 24 hour periods during
the 28-day treatment period.
Other Endpoints
Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24
hrs, 7 and 14 days of treatment).
Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.
Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.
Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.
Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.
Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint.
Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint.
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6.2.2.
Efficacy Assessments
6.2.2.1.
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On Day 1 (Visit 2) and Day 28 (Visit 5), in addition to the pre-dose measurement, serial
FEV1 measurements will be taken as outlined in Table 1. At each time point, the highest
of three technically acceptable measurements will be recorded.
FEV1 Stability Limit
For those subjects who are randomised, a FEV1 Stability Limit will be determined at
Visit 2. This will be calculated as follows:
Best pre-dose FEV1 at Visit 2 x 80%
6.2.2.2.
Response to salbutamol/albuterol
Following completion of the serial 24 hour FEV1 measurements at Visit 2 and Visit 5
(i.e. on Day 2 and Day 29), post salbutamol/albuterol FEV1 will be measured. The
assessment at Visit 2/2a will be made prior to the evening dose of study medication on
Day 2. The subject will be administered a single 400mcg dose of inhaled
salbutamol/albuterol via MDI or one nebulised salbutamol/albuterol solution and FEV1
will be measured 30 minutes after this administration. The highest of three technically
acceptable measurements will be recorded. These assessments will be performed as
follows:
6 hours after the last use of salbutamol/albuterol (compliance with this will be
recorded in the spirometry equipment).
24 hours after the first dose (Visit 2) or last dose (Visit 5) of study medication
For Visit 2/2a only, before the dose of study medication is taken on treatment Day 2.
6.2.2.3.
Diary Parameters
Throughout the study, including the run-in period and 7 day follow-up period, subjects
will record the following parameters in a Daily Diary:
Number of inhalations of rescue salbutamol/albuterol usage during the day and night
The use of the Daily Diary will be explained to the subject at Visit 1. Subjects will be
asked to return the Diary to the investigator at each clinic visit and the investigator or
his/her designee will review the data recorded. The investigator will ensure that the
subject is completing the Daily Diary correctly and will re-explain proper completion as
appropriate. At Visit 2, if the subject has been unable to complete the Daily Diary
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correctly, or is deemed non-compliant, the subject will be excluded from the study
(see Section 4.3, Exclusion Criteria and Section 4.4, Randomisation Criteria). In the
event there is a technical malfunction of the Daily Diary during the last week of the runin period, the run-in period can be extended for one additional week.
At Visit 3, 4 and 5, the investigator or his/her designee will review all data recorded in
the Daily Diary to confirm that the subject has not met the criteria for withdrawal due to
lack of efficacy (see Section 4.5, Withdrawal Criteria).
Subjects will be issued a paper medical conditions diary to record adverse events during
the study.
6.2.2.4.
Morning and evening peak expiratory flow will be measured using a peak flow meter that
will be issued to subjects at Visit 1. For each PEF measurement time point, three
measurements will be made (within 30 minutes of each other) and the highest will be
recorded in the Daily Diary. The best measurement at each time point will be used for
subsequent analyses. PEF will be measured each morning prior to any rescue
salbutamol/albuterol use and each evening prior to study medication dose and, if possible,
rescue salbutamol/albuterol use.
PEF Stability Limit
For those subjects who are randomised, a PEF Stability Limit will be calculated by the
Daily Diary. The Stability Limit will be calculated as follows:
Mean AM PEF from the available 7 days preceding Visit 2 x 80%
The AM PEF from the morning of Visit 2 will be included in the calculation of the PEF
stability limit.
The stability limit applies regardless of whether the PEF decrease has occurred in the AM
or PM PEF.
6.2.2.5.
Asthma symptom scores will be recorded twice daily in the Daily Diary before taking any
rescue salbutamol/albuterol or study medication (evening only) and prior to making the
PEF measurements. They will reflect the symptoms for the previous day and night and
will use the following scales:
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Subjects will be provided with salbutamol/albuterol MDIs for use as rescue medication
throughout the run-in period, study treatment period and follow-up period. Each morning
and evening, subjects will record in their Daily Diary the number of inhalations of
inhaled salbutamol/albuterol rescue medication used during the previous 12 hours. Use of
spacer devices is not permitted.
6.2.2.7.
Refer to Section 4.5, Withdrawal criteria for details on withdrawals due to lack of
efficacy.
6.3.
Safety
6.3.1.
Safety Endpoints
Vital signs (pulse rate and systolic and diastolic blood pressure) on Days 1, 7, 14 and
28.
The following endpoints will be derived:
Change from baseline in maximum value (0-4 hours) for systolic blood pressure
Change from baseline in minimum value (0-4 hours) for diastolic blood pressure
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Change from baseline in maximum value (0-4 hours) for pulse rate
Weighted mean change from baseline (0-4 hours) for blood pressure and pulse
rate.
Weighted mean change from baseline (0-4 hours) in the QTc(F) (QT interval
corrected by Fridericia's method)
Weighted mean change from baseline (0-4 hours) in QTc(B) (QT interval
corrected by Bazett's method)
Maximum change from baseline (0-4 hours) for QTc(F) and QTc(B).
Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on
Days 7 and 14 to derive the following endpoints:
6.3.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting
events that meet the definition of an AE or SAE.
6.3.2.1.
Definition of an AE
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Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
6.3.2.2.
Definition of a SAE`
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in
which the subject was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.
c.
d.
Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a persons ability to
conduct normal life functions. This definition is not intended to include experiences
of relatively minor medical significance such as uncomplicated headache, nausea,
vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which
may interfere or prevent everyday life functions but do not constitute a substantial
disruption.
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e.
f.
6.3.3.
ALT 5xULN.
Subjects with ALT 3xULN and <5xULN and bilirubin <1.5xULN, who do not exhibit
hepatitis symptoms or rash, can continue investigational product and be monitored
weekly for up to 4 weeks. At any point, if these subjects meet the liver chemistry
threshold stopping criteria (outlined above) or are unable to return for weekly liver
chemistries, investigational product must be permanently stopped, additional testing
performed, and the subject continue safety follow-up until liver chemistries resolve,
stabilize, or return to baseline values. The subject must then be withdrawn from the
study.
Subjects with ALT 3xULN and bilirubin 1.5xULN (>35% direct bilirubin; bilirubin
fractionation required) must be immediately and permanently withdrawn from
investigational product. Every attempt must be made to have the subject return to clinic
(within 24 hours) for repeat liver chemistries and additional testing, and monitored
closely (with specialist or hepatology consultation recommended). This event must be
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Hepatitis C RNA;
Hepatitis E IgM antibody (if subject resides outside the USA or Canada, or has
travelled outside USA or Canada in past 3 months)
Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last
dose. Record the date/time of the PK blood sample draw and the date/time of the last
dose of investigational product prior to blood sample draw on the CRF.
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The following are required for subjects with ALT 3xULN and bilirubin 1.5xULN but
are optional for other abnormal liver chemistries:
6.3.4.
From the time a subject consents to participate in and completes the study (including any
follow-up period), all SAEs assessed as related to study participation (e.g., protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK
concomitant medication, will be reported promptly to GSK. The time period for
collection of AEs will begin from the time of randomisation (first receipt of
investigational product) and will end after the 7 days follow-up period has been
completed.
From Visit 2 onwards (see Table 1), after the subject has had an opportunity to
spontaneously mention any changes in their medical condition, the investigator should
enquire whether the subject has had any AEs by asking the subject standard questions and
reviewing the subjects Daily Diary for evidence of any AEs.
Refer to Section 6.3.7 for reporting requirements for SAEs and other relevant events.
6.3.4.1.
Asthma Exacerbations
For the purposes of this study, a subject will be withdrawn due to lack of efficacy if they
experience a clinical exacerbation, or at the Investigators discretion. An exacerbation is
defined as worsening asthma requiring any treatment other than study medication or
rescue salbutamol/albuterol or the subjects regular inhaled corticosteroid use. This
includes requiring the use of systemic corticosteroids and/or emergency room visit or
hospitalisation or a change in inhaled corticosteroid dose.
Asthma exacerbations should not be recorded as an adverse event, unless they meet the
definition of a Serious Adverse Event (See Section 6.3.2.2). For the purposes of this
study, asthma exacerbations will be collected and recorded on the exacerbations log in
the eCRF. The time period for collection of asthma exacerbations will begin from the
time of randomisation (first receipt of investigational product) and will end after the 7
days follow-up period has been completed.
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Pregnancy
Any pregnancy that occurs during study participation (Visit 2 through to follow-up) must
be reported using a clinical trial pregnancy form. To ensure subject safety, each
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The
pregnancy must be followed up to determine outcome (including premature termination)
and status of mother and child. Pregnancy complications, and elective terminations for
medical reasons must be reported as an AE or SAE. Spontaneous abortions must be
reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigators
attention after the subject has completed the study and considered by the investigator as
possibly related to the investigational product, must be promptly reported to GSK.
In the event a subject becomes pregnant during the study they should discontinue taking
the study medication and be withdrawn from the study.
6.3.6.
Medical Devices
Medical devices (peak flow meters) are being provided by GSK for use in this study.
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SAEs, pregnancies, medical device incidents and near-incidents, and liver function
abnormalities meeting pre-defined criteria will be reported promptly to GSK as described
in the following table once the investigator determines that the event meets the protocol
definition for that event.
Initial Reports
Type of Event
All SAEs
Time Frame
24 hours
Pregnancy
2 Weeks
Liver chemistry
abnormalities:
ALT3xULN PLUS
Bilirubin1.5xULN)
Documents
SAE data
collection tool
Pregnancy Form
24 hours
Liver Chemistry
Report Form
24 hours
24 hours
ALT5xULN or
ALT3xULN with
hepatitis or rash or 4
weeks
24 hours
ALT3xULN and
<5xULN and bilirubin
<1.5xULN
Liver Chemistry
Report Form
24 hours
Liver Chemistry
Report Form
24 hours
Updated Liver
Chemistry Report
Form
Updated Liver
Chemistry Report
Form
Updated Liver
Chemistry Report
Form
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus
procedures for completing and transmitting SA reports to GSK are provided in the SPM.
Procedures for post-study AEs/SAEs are provided in the SPM.
6.3.8.
6.3.8.1.
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4 hours prior to the pre-dose blood samples and until after the 4hour post-dose blood
samples at Visits 2 and 5.
All blood samples will be sent to a central laboratory for analysis. Full details of the
collection and shipping requirements for the central laboratory are provided in the SPM.
A mid-stream urine sample will be collected as outlined in Table 1 for urinalysis tests.
These will be analysed in a central laboratory.
6.3.8.2.
ECG
12-lead ECGs will be measured by the investigator or his/her suitably qualified designee,
as outlined in Table 1. ECGs will be recorded after 5 minutes rest, after measurement of
vital signs and before clinic lung function tests at the specified time.
If the subject fails the lung function criteria at the first attempt, and only becomes eligible
for the study at the second screening visit the investigator must document the ECG results
are clinically acceptable within the 4 day screening period.
Investigators will be provided with ECG machines by GSK through a designated central
laboratory. Paper ECG traces will be recorded at a standard paper speed of 25mm/sec and
gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and
storage of the data by a validated method, with subsequent transferral to the central
laboratory for manual reading and calculation of the electrocardiographic parameters.
QTc(F) will be derived by the central laboratory using the manual calculations according
to the following formulae:
RR = (QT/QTc(B))2 and QTc(F) = QT/RR1/3
The manual reading and calculation of the ECG parameters will be used to determine
whether a subject meets the eligibility criteria for enrolment in the study at Visit 2.
The independent cardiologist, at the central laboratory, will be blinded to treatment
assignment and will be responsible for providing an official interpretation of all ECGs
collected in this study. A hard copy of these results will be sent to the study site.
Visit 2 pre-dose ECGs will be interpreted by the independent cardiologist as follows:
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If there is a discrepancy between the assessment of the investigator and that of the
independent cardiologist, the assessment of the independent cardiologist will be used in
all analyses and data presentations. If the pre-dose ECG at Visit 2 is judged to be
abnormal and clinically significant, the subject must be withdrawn from the study.
The independent cardiologist will determine whether the Visit 3, 4 and 5 pre-dose ECGs
(or ECG taken at the Early Withdrawal Visit) represents:
The independent cardiologist will determine whether the ECGs taken post-dose at Visit 2,
3, 4 and 5 represent:
no change or insignificant change from the pre-dose ECG for the corresponding visit
significant change (favourable) from the pre-dose ECG for the corresponding visit
significant change (unfavourable) from the pre-dose ECG for the corresponding visit
The ECG will be repeated at the Follow-up visit if it is clinically significantly abnormal
at Visit 5.
If any of the abnormalities in ECGs outlined in Section 4.5 (withdrawal criteria) are
observed pre-dose Visit 2 or after randomisation, the subject must be withdrawn from
treatment.
6.3.8.3.
Vital Signs
Sitting pulse rate and blood pressure measurements will be performed by the investigator
or his/her qualified designee, as outlined in Table 1. Measurements will be made with
the subject sitting, having rested in this position for at least 5 minutes before each
reading. They will be taken before measurement of any clinic lung function tests or
ECGs at the specified time point.
6.4.
Pharmacokinetics
6.4.1.
Pharmacokinetic Endpoint(s)
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A sparse sampling approach will be utilised. Blood samples (approximately 4mL) for the
determination of GW642444, the GW642444 metabolites (GW630200 and GSK932009)
and the triphenylacetate counter ion (GI179710) concentrations will be collected from all
subjects over 4 visits (Visits 2, 3, 4 and 5) as follows. The investigator will follow
guidance in the SPM for sample processing, storage and shipment.
Visits 2 and 5 (Days 1 and 28): Subjects will attend the evening clinic without having
taken their study medication. A pre-dose sample will be collected at the beginning of
their clinic visit. Additional samples will then be taken post-dose as indicated in Table 1.
Every attempt should be made to collect samples at times spread throughout the time
window (i.e. avoid collection from all subjects at the same times or extremes of the time
window).
Visit 3 (Day 7): Subjects will attend the evening clinic without having taken their study
medication. A pre-dose sample will be collected at the beginning of their clinic visit.
Visit 4 (Day 14): Subjects will attend the evening clinic without having taken their study
medication. One sample will be taken post-dose as indicated in Table 1. Every attempt
should be made to collect samples at times spread throughout the time window (i.e. avoid
collection from all subjects at the same times or extremes of the time window).
Only samples from subjects receiving GW642444 will be analysed for GW642444. By
first intent only samples from the highest dose group will be analysed for the metabolites
and the triphenylacetate counter-ion; if the majority (>80%) of samples are below the
lower limit of quantification (LLQ), samples from the remaining dose groups will not be
analysed. Personnel (WorldWide Bioanalysis, DMPK) involved in the bioanalysis of PK
samples will be unblinded as per GSK policy. Samples from subjects receiving placebo
will not be analysed.
At each visit, the exact time and date that the investigational product was taken on the
visit day and on the day prior to the visit will be recorded in the eCRF. The exact time
and date of the blood sample collection will also be documented in the eCRF.
6.5.
Pharmacodynamics
6.6.
Pharmacogenetics
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can be initiated. When PGx assessments will not be approved, then the approval for the
rest of the study will clearly indicate this and therefore, PGx assessments will not be
conducted.
7.
DATA MANAGEMENT
Data Management will identify and implement the most effective data acquisition and
management strategy for this clinical trial protocol and deliver datasets which support the
protocol objectives.
For this study subject data will be entered into GSK defined electronic case report forms
(eCRFs), transmitted electronically to GSK and combined with data provided from other
sources (eg Daily Diary data, laboratory data) in a validated data system.
Clinical data management will be performed in accordance with applicable GSK
standards and data cleaning procedures with the objective of removing errors and
inconsistencies in the data which would otherwise impact on the analysis and reporting
objectives, or the credibility of the Clinical Study Report. Adverse events and
concomitant medications terms will be coded using MedDRA and GSKDrug, an internal
validated medication dictionary. An appropriate medical dictionary that covers all
approved drugs in the region will be referenced. Original CRFs will be retained by GSK,
while the investigator will retain a copy. In all cases, subject initials will not be collected
nor transmitted to GSK.
8.
8.1.
Hypotheses
The primary efficacy endpoint is the change from baseline in clinic visit trough FEV1 at
the end of the treatment period and will be derived from the mean of the 23 and 24 hour
post-dose assessments on Day 28. The primary analysis will be a test of linear trend in
dose response to demonstrate overall efficacy of GW642444M relative to placebo. This
will be based on a two-sided hypothesis testing approach whereby the null hypothesis is
that the slope of the dose response relationship is zero. The alternative hypothesis is that
this slope is not zero.
Provided the test of linear trend is statistically significant, two-sided hypothesis tests of
each dose versus placebo will be performed to demonstrate superiority of individual
doses. The null hypothesis is that the effect of each dose regimen of GW642444M and
placebo on trough FEV1 is identical. The alternative hypothesis is that the dose regimens
of GW642444M and placebo have different effects on trough FEV1.
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8.2.1.
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8.3.
8.3.1.
Analysis Populations
Details of the derived data in analysis datasets to be created will be given in the
Reporting and Analysis Plan (RAP).
8.3.3.
Treatment Comparisons
8.3.3.1.
The primary treatment comparison is a test for linear dose response in trough FEV1
across the five doses of GW642444M and placebo in order to demonstrate overall
efficacy of GW642444M. If this test is statistically significant, each dose of
GW642444M will be compared with placebo to identify effective doses. These
comparisons will be performed by the use of hypothesis tests as described in Section 8.1.
These comparisons are to be performed using the ITT Population.
The primary analysis will be performed using Analysis of Covariance (ANCOVA) with
LOCF to impute missing data. A supporting analysis will also be performed using a
Repeated Measures Mixed Model. Missing data are not implicitly imputed in this
analysis, however, all non-missing data for a subject will be used within the analysis to
estimate the Day 28 treatment effects.
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A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance
level) is considered acceptable for this study. Since the pairwise comparisons with
placebo will only be performed if GW642444M is first shown to be efficacious relative to
placebo by means of the primary dose-response test, no further multiplicity adjustments
will be applied.
8.3.3.2.
The primary comparisons will be supported by the same tests performed using the
PP Population (i.e. pairwise comparisons will only be performed using the PP population
if they are performed for the ITT population). A linear trend test across the five active
doses of GW642444M but excluding placebo will also be performed to further explore
the dose response relationship of GW642444M. Tests of pairwise comparisons will be
performed for all the secondary and other efficacy endpoints.
8.3.4.
Interim Analysis
Where possible, data from subjects who withdraw prematurely from the study will be
included in any analyses. Specific details for inclusion will be detailed in the RAP, but in
general the minimum data required will be a baseline evaluation and at least one postbaseline evaluation. Missing trough FEV1 data at Day 28 will be imputed for the primary
analysis using LOCF. The primary endpoint will also be analysed using Repeated
Measures whereby missing data are not directly imputed but the correlation between
visits for all patients is used to adjust the estimate of treatment effect.
For the secondary endpoints relating to serial FEV1, the weighted mean will only be
calculated if there are at least 4 non-missing values in the time period of interest and the
subject has data for at least one time point between 0 and 4 hours, and either Hour 16 or
Hour 20, and either Hour 23 or Hour 24. The AUC will be calculated from the first nonmissing time point to the last non-missing time point. If an observation is missing
between two non-missing observations, the AUC will be interpolated between the two
non-missing values.
Secondary endpoints relating to Diary assessments will be calculated from all available
data over the period of interest. No imputations will be performed for missing data.
All hypothesis tests for main effects will use a 2-sided test at the 5% level of significance.
Any tests for interactions will be 2-sided at the 10% level of significance. We will
explore interactions with treatment as part of the model-checking process. In all cases, if
any assumptions of the proposed method of analyses are not met, alternative methods of
analyses will be used.
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It is anticipated that approximately 100 centres will participate in the study. Therefore, it
is likely that many centres will enrol very small number of subjects. Consequently, all
centres within the same country will be pooled and these amalgamations will be used
wherever pooled centre is incorporated into the analysis. If there are any countries
enrolling very small numbers in total (<12), these countries will be pooled with another
country within a similar geographical region. All amalgamations will be finalised and
documented prior to unblinding the treatment codes.
Baseline values for each endpoint will be those used as appropriate from either Visit 2 for
clinic visit endpoints or from the last 7 days of the Run-in Diary.
8.3.5.1.
Efficacy Analyses
All efficacy data will be summarised using means, standard deviations, medians and
ranges for continuous variables and frequencies and percentages for categorical variables.
Primary Analysis
The primary endpoint of change from baseline in trough FEV1 at the end of treatment
will be derived using the mean of the 23 and 24 hour post-dose FEV1 assessments. The
primary analysis will be performed using an ANCOVA model with effects due to
baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment group, imputing missing data using LOCF. A linear trend contrast will be
constructed to evaluate the dose response trend. The primary comparisons will also be
performed in a sensitivity analysis using a repeated measures model allowing for effects
due to baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum,
visit and treatment group. This model will also contain a visit-by-treatment interaction
term. A linear trend contrast will be constructed for Day 28 to evaluate the dose response
trend.
The estimated slope of the dose response will be presented together with a 95%
confidence interval (CI) for the slope and a p-value for the linear trend test. Estimated
treatment differences for all pairwise comparisons will be presented together with
95% CIs for the difference and p-values, provided the primary dose-response test is
statistically significant.
Secondary Analyses
Trough FEV1 Strata Analyses
The primary endpoint of change from baseline in trough FEV1 at the end of treatment
will also be analysed for each percent predicted FEV1 strata separately in order to
investigate the consistency of the dose response relationship for the different disease
severities. The same ANCOVA model as for the primary analysis will be used to estimate
the dose response slope and its 95% CI for each stratum. Statistical significance testing
will not be performed for the strata analyses.
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For the change between 24 hours after dosing on Day 1 (Visit 2) and Day 28 (Visit 5), the
difference between:
and
will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model with effects due to baseline, centre grouping,
age, sex, baseline percent predicted FEV1 stratum and treatment. Estimated treatment
differences for all comparisons will be presented together with 95% CIs for the difference
and p-values.
Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose
of 400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after
dosing on Day 1 (Visit 2)
For the change between pre-dosing (Visit 1) and 24 hours after dosing on Day 1 (Visit 2),
the difference between:
and
will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model as described above for the change between
Day 1 and Day 28.
Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose
of 400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after
dosing on Day 28 (Visit 5)
For the change between pre-dosing (Visit 1) and 24 hours after dosing on Day 28
(Visit 5), the difference between:
and
will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model as described above for the change between
Day 1 and Day 28.
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Other Analyses
The reporting and analysis of other endpoints as specified in the protocol will be provided
in the RAP.
8.3.5.2.
Safety Analyses
Extent of Exposure
The extent of exposure to study drug will be summarised by treatment group.
Adverse Events (AEs)
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory
Activities (MedDRA), and grouped by body system. AEs occurring pre-treatment, during
active treatment and post-treatment will be summarised separately. The number and
percentage of subjects experiencing at least one AE of any type, AEs within each body
system and AEs within each preferred term will be presented for each treatment group.
Separate summaries will be provided for all AEs, AEs by maximum severity, drug related
AEs, SAEs, and for AEs leading to withdrawal.
Deaths and SAEs
All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be
documented in case narrative format.
Clinical Laboratory Evaluations
Clinical laboratory evaluations, including haematology, clinical chemistry and dipstick
urinalysis parameters, will be summarised by treatment group using shift tables and
summary statistics for each visit at which these parameters are collected. Baseline will be
defined as the Visit 1 value. Further details will be provided in the RAP.
Vital Signs Assessments
Vital signs (pulse rate, systolic blood pressure and diastolic blood pressure) will be
summarised by treatment for each clinic visit. Further details will be provided in the
RAP. Additionally, the derived vital signs endpoints of:
Change from baseline in maximum value (0-4 hours) for systolic blood pressure
Change from baseline in minimum value (0-4 hours) for diastolic blood pressure
Change from baseline in maximum value (0-4 hours) for pulse rate
Weighted mean change from baseline (0-4 hours) for blood pressure and pulse
rate.
on Day 1, Day 7, Day 14 and Day 28 will be analysed using ANCOVA with effects due
to baseline value, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment. Baseline will be defined as the Visit 2 pre-dose value. Pairwise comparisons
of each active treatment group versus placebo will be performed.
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12-Lead ECG
12-Lead ECG data will be summarised by treatment using shift tables and summary
tables for Day 1, Day 7, Day 14 and Day 28. Weighted mean change from baseline and
maximum change from baseline in QTc(F) and QTc(B) 0-4 hours post-dose will be derived
on Day 1, Day 7, Day 14 and Day 28, where baseline will be defined as Visit 2 pre-dose,
and will be analysed using ANCOVA as for the derived vital signs endpoints. Pairwise
comparisons of each active treatment group versus placebo will be performed.
Fasting Blood Glucose and Potassium
Fasting plasma glucose and serum potassium data will be summarised by treatment using
shift tables and summary tables for Day 1 and Day 28 and for non-fasting potassium on
Day 7 and 14. Weighted mean change from baseline in glucose and potassium 0-4 hours
post-dosing, maximum decrease from baseline in potassium 0-4hours post-dosing, and
maximum increase from baseline in glucose 0-4hours post-dosing will be derived on Day
1, Day 7, Day 14 and Day 28 (potassium; non fasting potassium on Day 7 and 14) and
Day 1 and Day 28 (glucose), where baseline will be defined as Visit 2 pre-dose, and will
be analysed using ANCOVA as for the derived vital signs endpoints. Pairwise
comparisons of each active treatment group versus placebo will be performed.
8.3.5.3.
Pharmacokinetic Analyses
The GW642444 plasma concentration data will be analysed using nonlinear mixed
effects modeling. The effect of demographic factors and concomitant medications on the
pharmacokinetics will be examined.
GW630200, GSK932009 and counter-ion in plasma concentration data will be analysed
as appropriate.
8.3.5.4.
Pharmacodynamic Analyses
Pharmacokinetics/Pharmacodynamics Analyses
The relationship between selected endpoints (including heart rate, glucose and potassium)
and systemic exposure to GW642444 will initially be explored graphically. Assessment
of pharmacokinetic/pharmacodynamic relationships may be undertaken via formal
modelling approaches as data permits. A population non linear mixed-effect dose
response analysis may be performed using trough FEV1 data if statistical analysis show
highly non linear trend (such as physiological Emax or variants). Various PD models
including step, step-linear or variant Emax models will be explored.
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9.
9.1.
Prior to initiation of a study site, GSK will obtain approval from the appropriate
regulatory agency to conduct the study in accordance with applicable country-specific
regulatory requirements, including those required under a US IND.
The study will be conducted in accordance with all applicable regulatory requirements,
including a U.S. IND.
The study will be conducted in accordance with Good Clinical Practice (GCP), all
applicable subject privacy requirements, and the guiding principles of the declaration of
Helsinki, including, but not limited to:
GSK will provide full details of the above procedures, either verbally, in writing, or
both.
Written informed consent must be obtained from each subject prior to participation
in the study.
9.2.
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors
will contact the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK
requirements. When reviewing data collection procedures, the discussion will include
identification, agreement and documentation of data items for which the CRF will serve
as the source document.
GSK will monitor the study to ensure that the:
Study is conducted in accordance with the currently approved protocol and any other
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to
allow the monitor direct access to all relevant documents
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Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may
conduct a quality assurance audit of the site records, and the regulatory agencies may
conduct a regulatory inspection at any time during or after completion of the study. In the
event of an audit or inspection, the investigator (and institution) must agree to grant the
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their
time and the time of their staff to discuss any findings/relevant issues.
9.4.
Upon completion or termination of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff (as appropriate), in accordance with applicable
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for
reasons including (but not limited to) safety issues, ethical issues, or severe
noncompliance. If GSK determines that such action is required, GSK will discuss the
reasons for taking such action with the investigator or head of the medical institution
(where applicable). When feasible, GSK will provide advance notice to the investigator
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all
investigators, heads of the medical institutions (where applicable),and/or institutions
conducting the study. GSK will also promptly inform the relevant regulatory authorities
of the suspension/termination along with the reasons for such action. Where required by
applicable regulations, the investigator or head of the medical institution must inform the
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.5.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where
applicable) must maintain all site study records (except for those required by local
regulations to be maintained elsewhere) in a safe and secure location. The records must
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and
must be available for review in conjunction with assessment of the facility, supporting
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the
records may be maintained in a format other than hard copy (e.g., microfiche, scanned,
electronic); however, caution must be exercised before such action is taken. The
investigator must ensure that all reproductions are legible and are a true and accurate
copy of the original. In addition, they must meet accessibility and retrieval standards,
including regeneration of a hard copy, if required. The investigator must also ensure that
an acceptable back-up of the reproductions exists and that there is an acceptable quality
control procedure in place for creating the reproductions.
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GSK will inform the investigator of the time period for retaining the site records in order
to comply with all applicable regulatory requirements. The minimum retention time will
meet the strictest standard applicable to a particular site, as dictated by local
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including,
but not limited to archival of records at an off-site facility or transfer of ownership of the
records in the event that the investigator is no longer associated with the site.
9.6.
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REFERENCES
American Thoracic Society (ATS), Centres for Disease Control and Prevention.
Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases
Society of America. Morbidity and Mortality Weekly Report. 2003;52:RR-11 (1-74).
American Thoracic Society Documents. American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis
in the United States. Am J Respir Crit Care Med. 2005;172:1169-1227.
GlaxoSmithKline Document Number RM2003/00283/00 Study ID GlaxoSmithKline
Document No. A randomized, double-blind, placebo-controlled, parallel group, 12-week
trial evaluating the efficacy and safety of the fluticasone propionate/salmeterol
DISKUS combination product 250/50mcg once daily versus fluticasone
propionate/salmeterol DISKUS combination product 100/50mcg twice daily versus
fluticasone propionate DISKUS 250mcg once daily versus placebo in symptomatic
adolescent and adult subjects with asthma that is not controlled on short-acting beta2agonists alone. Report Date 2004.
GlaxoSmithKline Document Number RM2007/00094/00 Study ID GW642444.
Supplement to GW642444 Investigator's Brochure. Report Date Oct-2007.
GlaxoSmithKline Document Number SM2003/00028/05 Study ID GW642444.
Investigator's brochure for GW642444 a selective beta-2 adrenoceptor agonist. Report
Date 29-Jun-2007.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and
Prevention 2006. Global Initiative for Asthma, www.ginasthma.org; 2006.
Hankinson J L, Odencrantz, JR; Feden, KB. Spirometric Reference Values from a
Sample of the General U.S. Population. AM J Respir Crit care Med. 1999;159:179-187.
National Institutes of Health (NIH). The Seventh Report of the Joint National Committee
on Prevention, Detection, and Treatment of High Blood Pressure. National Heart, Lung,
and Blood Institute, U.S. Department of Health and Human Services; 2004. 04-5230.
NIH. Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NHLBI,
August; 2007. NIH publication no. 08-4051.
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11.
APPENDICES
11.1.
Appendix 1: PGx
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Pharmacogenetic Research
Pharmacogenetics Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary
factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution,
metabolism, elimination), pharmacodynamics (relationship between concentrations and
pharmacologic effects or the time course of pharmacologic effects) and/or clinical
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of
PGx analysis include:
Drug
Abacavir
Tranilast
ABT-761
Disease
HIV
[Hetherington, 2002;
Mallal, 2002]
Restenosis
prevention following
coronary bypass
[Roses, 2002]
Asthma
[Drazen, 1999]
Gene
HLA (human
leukocyte
antigen)
UGT1A1
Outcome
Caucasian males with HLA B57 variant were
at increased risk for experiencing
hypersensitivity to abacavir
Drug induced hyperbilirubinemia explained by
high proportion of affected patients having 7/7
TA repeat genotype, consistent with clinically
benign Gilberts Syndrome
ALOX5 Sp1 promoter genotype (x,x)
associated with reduced response to 5lipoxygenase inhibitor ABT-761
ALOX5
A key component to successful PGx research is the collection of samples during the
conduct of clinical studies.
Pharmacogenetics (PGx) is the study of variability in product response due to hereditary
factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e. his or her genotype) may impact product response or clinical outcome
as well as disease susceptibility and the progression of that disease.
If at any time it appears that there is a potential unexpected or unexplained variation in
response to or handling of GW642444M (e.g., pharmacokinetics, efficacy and/or safety)
that may be attributable to genetic variation, then PGx analysis may be conducted. In
these circumstances, the analysis undertaken will be limited to PGx analysis of
GW642444M handling or response and may include the evaluation of specific candidate
genes, the conduct of a whole genome single nucleotide polymorphism (SNP) scan or
other marker scan.
Although a heterogeneous therapeutic response to 2-agonists in asthma is well known,
the relative contribution of genetic (e.g., ADBR2 polymorphisms) and nongenetic (e.g.,
environmental exposures) parameters to this variability remains poorly defined. The 2adrenergic receptor is a 413 amino acid protein encoded for by an intronless gene
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ADRB2) located on chromosome 5q31.32 2. Variation in the activity of this cell surface
receptor is important because it mediates the effects of 2-agonists.
Numerous reports from clinical studies characterizing specific associations between
ADRB2 SNPs and therapeutic outcomes suggest that genetic variation can influence the
response to a variety of 2-agonists, but the clinical significance of these observations is
not yet clear. Screens of ADRB2 have identified polymorphisms which may influence
response to 2-agonists [Israel, 2000; Reishaus, 1983]. In particular, the receptor variant
characterized by substitution of arginine for glycine at position 16 (Gly16Arg) may be an
important determinant of receptor function in vitro and occurs commonly in the
population (minor allele frequency approximately 0.4-0.5). In addition, genome screening
of large asthma and COPD disease populations has identified putative respiratory disease
susceptibility genes and these genes may also influence drug response.
A whole blood sample will be collected (in addition to any blood samples to be taken for
the clinical study) at randomisation or during the study from all consenting subjects.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained
variation) is to investigate a possible genetic relationship to handling or response to
GW642444M. If at any time it appears there is potential variability in response in this
clinical study or in a series of clinical studies with GW642444M that may be attributable
to genetic variations of subjects, the following objectives may be investigated:
Study Population
Any subject who has given informed consent to participate in the clinical study, has met
all the entry criteria for the clinical study, and receives investigational product may take
part in the PGx research. Any subject who has received an allogeneic bone marrow
transplant must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty
or loss of benefits to which the subject would otherwise be entitled.
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If a subject withdraws consent from the PGx research or requests sample destruction for
any reason, the investigator must complete the appropriate documentation to request
sample destruction within the timeframe specified by GSK and maintain the
documentation in the site study records. In either case, GSK will only keep study
information collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the
subject does not meet the entry criteria for participation in the clinical study, then the
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Specific sections of DNA may be selected from areas of the genome (e.g., candidate
genes) known to encode the drug target, drug metabolizing enzymes, areas
associated with mechanisms underlying adverse events, and those linked to study
disease and, thus, linked to drug response. The candidate genes that may be
investigated in this study will include the following: the GSK Absorption,
Distribution, Metabolism and Excretion (ADME) panel. Absorption, distribution,
metabolism and excretion (ADME) genes play a central role in drug
pharmacokinetics and pharmacodynamics (PK-PD). The GSK ADME panel
contains genetic markers from one hundred and thirty-five enzymes, transporters and
other genes involved in drug absorption, distribution, metabolism and excretion. The
ADME panel may be used to investigate the relationship between genetic variants on
the panel and pharmacokinetics, safety and efficacy of the investigational product.
The candidate genes that may be investigated include, but may not be limited to the 2adrenoceptor (ADRB2). In addition, continuing research may identify other proteins that
may be involved in the response to GW642444M. The genes that encode these proteins
may also be studied.
In addition, continuing research may identify other enzymes, transporters, proteins, or
receptors that may be involved in response to GW642444M. The genes that may code
for these proteins may also be studied.
1
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Analytes to be included in haematology panel - Haemaglobin, Red Blood Cells, Mean Cell Volume,
Mean Cell Haemoglobin, Mean Cell Haemoglobin Concentration, Haematocrit, Platelets, White
Blood Cells.
Differential white cell count: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils
Analytes to be included in chemistry panel - Urea, Creatinine, Uric acid, Direct and Indirect
bilirubin, Total bilirubin, Total protein, Albumin, Creatinine kinase, Alkaline Phosphatase, Aspartate
Aminotransferase, Alanine Aminotransferase, Lactate Dehydrogenase, Gamma Glytamyl
Transferase, Glucose, Potassium, Sodium, Calcium, Chloride
Analytes to be included in urinalysis dipstick if abnormal standard panel for microscopy
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Clarification that upper and lower respiratory tract infections are only an exclusion
criterion if they have resulted in a change to subjects asthma management or if they
affect the subjects ability to participate in the study.
Clarification that subjects with severe milk protein allergy should be excluded from
the study as per exclusion criterion No. 7. The protocol has been amended to make
this point explicit.
Clarification that long acting anti-histamines only are prohibited for 14 days prior to
and during the study. This is currently inconsistent within the protocol.
It is no longer necessary for Investigators to consult with the GSK Medical Monitor
prior to withdrawing a subject who has met any of the ECG withdrawal criteria.
Clarification that study issued rescue salbutamol/albuterol will be provided for use
during the run-in, treatment period and follow-up period. This is currently
inconsistent within the protocol.
Protocol Changes
Revised Text
1.
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7.
Any adverse reaction including immediate or delayed hypersensitivity to any 2agonist or sympathomimetic drug, or known (i.e., patients with a history of severe
milk protein allergy) or suspected sensitivity to the constituents of GW642444M
inhalation powder (e.g., lactose or magnesium stearate).
Theophyllines
Slow-release bronchodilators
Oral antihistamines
Revised Text
12. Administration of the following asthma medications within 14 days of Visit 1:
Theophyllines
Slow-release bronchodilators
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A subject experiences any of the following abnormalities in ECGs:
Revised Text
The following asthma medications are permitted:
In addition, a subject may not concurrently use any other prescription or over-thecounter medication which may affect the course of asthma, or interact with
sympathomimetic amines, such as:
Polycyclic antidepressants
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Within 12 weeks of Visit 1:
In addition, a subject may not concurrently use any other prescription or over-the-counter
medication which may affect the course of asthma, or interact with sympathomimetic
amines throughout the study (Visit 1 to Visit 6 inclusive), such as:
Polycyclic antidepressants
Phenothiazines
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Corrected to indicate that rescue salbutamol/albuterol should be collected at the followup visit, not Visit 5/5a
Procedures
Visit
Day
Screen/
Run-in
1
-14(-
Treatment
2/2A1
1
Early
Withdrawal
3
7 (-4/+2)
4
14(-4/+2)
5/5A1
28(-4/+2)
6
D28 + 7(-
4/+2)
Written Informed
x
Consent
Subject Demography x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination x
Inclusion/Exclusion
x
Criteria
Randomisation
Criteria
Efficacy Assessments
Clinic measured FEV1 x
FEV1 response to
x
salbutamol/albuterol
x
Issue Diary and PEF
meter9
Review Diary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
Serum Pregnancy
x
Test
Urine pregnancy Test
HBsAg and hepatitis
x
C antibody
Exploratory Lab Assessments
PK sampling6
Serum potassium
and plasma glucose
sampling
Follow-up
4/+2)
x
x2
x3
x2
x2
x2
x3
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x4
x4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x5
x
x7
x10
x
X11
x
X11
x
x7
Continued
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Procedures
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Treatment
Early
Withdrawal
Followup
Investigational product
Dispense Invest.
x
Product.
Assess Invest.
x
x
x
x
Product compliance
Collect invest.
x
x
product
Issue rescue
x
x8
x8
salbutamol/albuterol
Collect used rescue
x
x
x
salbutamol/albuterol
1. Visit 2/2A and Visit 5/5A will take place over 2 days. In selected centres, subjects will be required to remain in the
clinic overnight (~50% of subjects). In other centres, subjects will return to the clinic approximately mid-morning
on Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements
2. On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 to be made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours post-dose. Measurements at 6 and 12 hours post-dose
will only be made in those subjects remaining at the clinic overnight On Days 7 (Visit 3) and 14 (Visit 4) pre-dose
FEV1 measurements required only
3. To be performed 24 hours after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of investigational product
4. Measurements to be made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose,
10minutes and 1, 2 and 4 hours post-dose
5. Samples should be taken pre-dose
6. Samples to be taken as follows:
Day 1 (Visit 2): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
Day 7 (Visit 3): pre-dose
Day 14 (Visit 4): 2minutes -1hour post-dose
Day 28 (Visit 5): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
7. Samples will be taken pre-dose and 10 minutes, 1, 2 and 4hours post-dose. Subject will be fasted from at least 4
hours prior to the pre-dose blood sample until after the 4 hour post-dose sample
8. If required
9. Morning and evening PEF, symptoms and rescue medication usage to be recorded every day from Visit 1 through
Visit 6
10. To be taken 24hours post-dose Day 28
11. Serum potassium only. Samples to be taken pre-dose and 10minutes, 1, 2 and 4 hours post-dose. Subjects are
not required to fast for these samples.
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Protocol Amendment 02
Protocol Changes
SCOPE: This amendment applies to all sites
Protocol changes specified in Amendment No. 02 are summarised as follows:
To allow subjects to re-screen for Visit 1 if they fail to meet lung function criteria
and to allow subjects who previously failed screening to be re-screened.
To clarify the exclusion of subjects with upper and lower respiratory tract infections
between Visit 1 and Visit 2 (Randomisation to Treatment).
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This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group
study. Subjects meeting all entry inclusion criteria and none of the exclusion criteria
during the Visit 1 screening period (no longer than 4 days) will enter a two week run-in
period and those who then fail to meet eligibility criteria for randomisation will be
withdrawn from the study.
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4. Subjects with current reversible airways disease as demonstrated at Visit 1 screening
period by an increase in FEV1 of 12% and 200ml over the presalbutamol/albuterol FEV1 at approximately 30 minutes after the inhalation of
400mcg of salbutamol/albuterol via MDI (spacer permitted for reversibility testing
only if required) or one nebulised salbutamol/albuterol solution.
Re-screening of subjects during the Visit 1 screening period: If a subject does not
meet the inclusion criteria based upon FEV1 percent predicted and/or reversibility, the
subject may return to the site once within 4 days and repeat the lung function tests.
The list of additional excluded conditions/diseases includes, but is not limited to the
following:
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Theophyllines
Slow-release bronchodilators
Revised wording
5
Participated in any study using an investigational drug during the previous 30 days or
will participate simultaneously in another clinical trial.
The list of additional excluded conditions/diseases includes, but is not limited to the
following:
systolic blood pressure 160, or diastolic blood pressure >100 2 or more measurements with systolic blood
pressure 160mmHg or diastolic blood pressure 100mmHg [NIH, 2004]
history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission =
no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an
approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be
enrolled [American Thoracic Society Documents, 2005; American Thoracic Society, 2003]
Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic
fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.
Theophyllines
Slow-release bronchodilators
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Ventricular rate < 45 beats per minute or > 90 beats per minute
Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
Incomplete right bundle branch block (QRS interval > 100msec < 120msec with
right bundle branch block pattern)
Revised Wording
5
Ventricular rate < 45 beats per minute or > 90 beats per minute
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Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.
Original Wording
7
Revised Wording
7
Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.
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Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
Incomplete right bundle branch block (QRS interval > 100msec < 120msec with
right bundle branch block pattern)
Revised text
A subject experiences any of the following abnormalities in ECGs. (the decision should
be made following consultation with the medical monitor, unless there is an immediate
safety concern and this is not feasible).
Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.
Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.
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Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.
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Revised text
Standard Deviation (ml)
400
415
430
440
450
460
Protocol Amendment 3
This amendment applies to all sites
Scope
Correction of an error in the text of Randomisation Criterion No. 7
Section 4.4. Randomisation Criteria
Original Text
7. Occurrence of a culture-documented or suspected bacterial or viral infection of the
upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a
change in asthma management, or in the opinion of the Investigator is expected to affect
the subjects asthma status or the subjects ability to participate in the study.
Revised text
7. No occurrence of a culture-documented or suspected bacterial or viral infection of the
upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a
change in asthma management, or in the opinion of the Investigator is expected to affect
the subjects asthma status or the subjects ability to participate in the study.
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18-Aug-2008
Description:
This is a Phase IIb multi-centre, randomised, double-blind, parallel-group, placebocontrolled study to evaluate the dose response, efficacy and safety of GW642444M
Inhalation Powder administered once daily in the evening at doses of 3mcg, 6.25mcg,
12.5mcg, 25mcg and 50mcg versus placebo in adolescent and adult subjects 12 years of
age and older with persistent asthma.
Subjects meeting the inclusion criteria at Visit 1 (screening visit, start of run-in) will
complete a 14 day pre-treatment run-in period. The run-in period is provided for
completion of baseline safety evaluations and to obtain baseline measures of asthma
status. Subjects will remain on their current inhaled corticosteroid therapy (at fixed
doses) throughout the study (screening to follow-up inclusive).
Subjects who meet the eligibility criteria for randomisation to study treatment will be
stratified in an approximately 1:1 ratio according to their baseline FEV1 as a percentage
of predicted normal. There will be one stratum for those with FEV1 percent predicted
40% - 65% and one for those with FEV1 percent predicted > 65%-90%. Once
stratified, subjects will be randomised to one of the six treatments and enter into a 28 day
double-blind treatment period. There will be a 7 day follow-up period following the end
of the treatment period. A subject will be regarded as having completed the study if they
complete all phases of the study (screening, treatment period and follow-up). Subjects
who complete the study will, therefore, participate in the study for a total of 7 weeks.
The primary efficacy measure will be the mean change from baseline at the end of the 28
day treatment period in trough (pre-bronchodilator and pre-dose) evening (PM) FEV1
derived from the mean of the 23 and 24 hour post-dose assessments. Secondary efficacy
measures include change from baseline in weighted mean for 24 hour serial FEV1 on
Days 1 and 28, mean change from baseline in daily trough PM PEF, mean change from
baseline in daily morning (AM) PEF, mean change from baseline in the percentage of
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symptom-free 24 hour periods, mean change from baseline in the percentage of rescuefree 24 hour periods, and the difference in post salbutamol/albuterol FEV1.
Safety assessments include adverse events, clinical laboratory evaluations, ECGs and
vital signs. Blood samples will be taken from all subjects for pharmacokinetic analysis
and from those who have consented for pharmacogenetic analysis.
Identifier/Version Number: YM2007/00064/01
Subject: Asthma, GW642444M, dose-ranging, efficacy, safety, pharmacokinetics,
placebo, PM Dosing
Authors Name, Title and Functional Area:
Principal Statistician, Respiratory MDC S&P
Statistician, Respiratory MDC S&P
Approved by:
Date
Senior Statistician
Respiratory MDC S&P
Date
Biostatistics and Programming Manager
Respiratory MDC S&P
Date
Director, Clinical Development
MDC Clinical Respiratory
BM BCh
Director, Clinical Development
MDC Clinical Respiratory
Date
Date
Clinical Pharmacokineticist
CPDM, UK
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Summaries were added of the cumulative proportion of subjects obtaining both 200mL
and 12% increase from baseline in FEV1 (0-4hr) up to and including each time point.
Summaries of the proportion and cumulative proportion of subjects obtaining 15%
increase from baseline in FEV1 (0-4hr) were added.
Peak FEV1 and Peak to Trough FEV1 Ratio
The calculation and analysis of peak post-dose FEV1 (0-4 hrs) and peak to trough FEV1
ratio have been added.
Baseline Values for ECG and Vital Signs
When determining the baseline value for ECG and vital signs, if the value at Visit 2 predose is missing then the screening value will be used in its place.
Adverse Events
A statement has been added that there will not be a summary of adverse events by
maximum severity.
Vital Signs
Summaries of the derived vital signs endpoints were added, along with summaries of
change from pre-dose.
QTc
Summaries and analyses of post-dose serial QTc(F) and QTc(B) were added.
Scatterplots of serial QTc(F) and QTc(B) versus heart rate from the ECG were added.
Summaries of weighted mean change from pre-dose QTc(F) and QTc(B) were added.
Potassium and Glucose
Summaries were added for change from baseline and change from pre-dose in the derived
potassium and glucose endpoints.
Clinical Pharmacology Data Analyses
Rewording of text in Section 13 to further clarify intent to conduct population
pharmacokinetic, systemic PK/PD, dose-response and K/PD modelling, if appropriate.
Clarification that systemic PK/PD modelling will only be formally investigated if the
treatment differences for the pairwise comparisons for each treatment group vs placebo
for systemic PD endpoints are statistically significant. Update to tables, figures, listings
and file specifications within Attachments to reflect changes in Section 13.
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................8
1.
INTRODUCTION.................................................................................................... 10
2.
3.
4.
5.
6.
7.
TREATMENT COMPARISONS.............................................................................. 17
7.1.
Primary Comparisons ................................................................................. 17
7.2.
Other Comparisons of Interest .................................................................... 17
7.3.
Data Display Treatment and Other Sub-group Descriptors ......................... 18
8.
9.
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9.2.
9.3.
9.4.
9.5.
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12.7.5.
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ABBREVIATIONS
AAUCMB
AE
ALT
AM
ANCOVA
AST
ATC
BMI
CA
CI
CPDM
CSR
DBF
DBR
df
dp
DPI
DS
ECG
eCRF
EVID
FDA
FEV1
GSK
HARP
hr
ICS
IDSL
ITT
L
LFT
LLQ
LOCF
LS
Max.
mcg
MDC
MedDRA
Min.
mL
N
n
NONMEM
NQ
OD
PD
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PEF
PGx
PK
PM
PP
QD
RAP
QTc(B)
QTc(F)
RAP
S&P
SD
Std Err
UCSF
UK
US
WWD
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Trademark Information
Trademarks not owned by the
GlaxoSmithKline group of companies
NONMEM
SAS
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INTRODUCTION
The analyses described in this document are for inclusion in a Clinical Study Report
(CSR). This Reporting and Analysis Plan (RAP) describes all planned analyses that will
be conducted and presented for B2C109575 and is based upon Section 8 (Data Analysis
and Statistical Considerations) in the B2C109575 protocol [GlaxoSmithKline Document
Number GM2006/00690/03].
This RAP was based on Instructions INS-WWD-4000-v04 effective from 26 June 2008.
2.
2.1.
Study Objective(s)
2.1.1.
Primary
The primary objective of this 28 day study is to evaluate the dose response, efficacy and
safety of five doses of GW642444M (3mcg, 6.25 mcg, 12.5 mcg, 25mcg and 50 mcg)
administered once daily in the evening in adolescent and adult subjects 12 years of age
and older with persistent asthma to effectively select the appropriate dose of
GW642444M to be evaluated in further clinical studies.
2.1.2.
Secondary
2.2.
Study Endpoint(s)
2.2.1.
Mean change from baseline to the end of the 28-day treatment period (last
assessment on treatment using last observation carried forward) in trough (PM prebronchodilator and pre-dose) FEV1. The trough FEV1 will be defined as the mean of
the FEV1 values obtained 23 and 24 hours after dosing on Day 28.
2.2.2.
Change from baseline in weighted mean for 24 hour serial FEV1 on Days 1 and 28
(mean post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23
and 24 hours);
Note: this endpoint will be derived for all subjects but the 6 and 12 hour time points
will only be measured in a sub-group of subjects (approximately 50% of subjects);
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Mean change from baseline in daily morning (AM) PEF averaged over the 28-day
treatment period;
Mean change from baseline in the percentage of rescue-free 24-hour periods during
the 28-day treatment period;
2.2.3.
Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24
hrs, 7 and 14 days of treatment);
Mean change from baseline in the percentage of symptom-free days during the 28day treatment period;
Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period;
Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period;
Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period;
Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint;
Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint;
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2.2.4.
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The following endpoints that were not specified in the protocol have been added:
Weighted mean change from baseline (0-4 hours) for FEV1 on Days 1 and 28;
Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 will be defined as the
mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28, with no
imputation.
2.2.5.
Safety Endpoints
Assessment of vital signs (pulse rate and systolic and diastolic blood pressure) on
Days 1, 7, 14 and 28.
Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on
Days 7 and 14 to derive the following endpoints:
Maximum decrease from baseline (0-4hr) for potassium
Weighted mean change from baseline (0-4hr) for potassium
Maximum increase from baseline (0-4hr) for glucose
Weighted mean change from baseline (0-4hr) for glucose;
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2.3.
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Statistical Hypotheses
The primary efficacy endpoint is the change from baseline in clinic visit trough FEV1 at
the end of the 28-day treatment period and will be derived from the mean of the 23 and
24 hour post-dose assessments on Day 28. The primary analysis will be a test of linear
trend in dose response to demonstrate overall efficacy of GW642444M relative to
placebo. This will be based on a two-sided hypothesis testing approach whereby the null
hypothesis is that the slope of the dose response relationship is zero. The alternative
hypothesis is that this slope is not zero.
H 0 : dose = 0
H 1 : dose 0
Provided the test of linear trend is statistically significant, two-sided hypothesis tests of
each dose versus placebo will be performed to demonstrate superiority of individual
doses over placebo and to aid selection of the optimum dose. The null hypothesis is that
the effect of each dose regimen of GW642444M and placebo on trough FEV1 is
identical. The alternative hypothesis is that the dose regimens of GW642444M and
placebo have different effects on trough FEV1.
H 0 : GW PBO = 0
H 1 : GW PBO 0
Since the pairwise comparisons with placebo will only be performed if the trend test
demonstrates overall efficacy of GW42444M, no further multiplicity adjustments are
required.
2.4.
3.
STUDY DESIGN
This is a Phase IIb multi-centre, randomised, placebo-controlled, double-blind, parallelgroup study to evaluate the dose response, efficacy and safety of five doses (3mcg, 6.25
mcg, 12.5 mcg, 25mcg and 50 mcg) of GW642444M over a 28 day treatment period in
adolescent and adult subjects with persistent asthma. Approximately 1200 subjects will
be screened to achieve 594 evaluable subjects (with at least one pre-dose or 23-24 hour
post-dose FEV1 assessment on or after nominal Day 7) or 99 subjects per group.
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Subjects will attend the clinic on 6-8 occasions during the study according to the schedule
given in Table 1.
Table 1
Randomised Treatment
GW642444M 3mcg once daily
GW642444M 6.25mcg once daily
Run-in
Follow-up
Clinic Visit:
Study Days:
-14
2/2A*
1/2
3
7
4
14
5/5A
28/29
(+7)
* Randomisation
All subjects will be dosed using the Novel Dry Powder Inhaler (DPI).
Subjects meeting all of the inclusion criteria and none of the exclusion criteria at the Visit
1 clinic visit (screening visit, start of run-in) will complete a 14(-4/+2) day pre-treatment
run-in period. The run-in period is provided for completion of baseline safety evaluations
and to obtain baseline measures of asthma status. Subjects will remain on their current
inhaled corticosteroid therapy (ICS) (at fixed doses) throughout the study (screening to
follow-up inclusive). At the end of the follow-up period, subjects will be prescribed
appropriate alternative asthma therapy, if required. Subjects who fail to meet eligibility
criteria for randomisation at visit 2 will be withdrawn from the study. Those subjects who
meet the eligibility criteria at the end of the run-in period will be stratified in an
approximately 1:1 ratio according to their baseline FEV1 as a percentage of predicted
normal. There will be one stratum for those with FEV1 percent predicted 40% - 65%
and one for those with FEV1 percent predicted > 65% - 90%. Once stratified, subjects
will be randomised to one of the six treatments and enter into a 28 day double-blind
treatment period (-4/+2days). Subjects will then attend 3 on-treatment visits at Visits 3, 4
and 5 (days 7, 14 and 28, respectively). The first dose of study medication will be given
in the clinic at the Visit 2 clinic visit.
There will be a 7 day follow-up period following the end of the treatment period. A
subject will be regarded as having completed the study if they complete all phases of the
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study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.
Further details of the study design can be found in Section 3 (Investigational Plan) of the
B2C109575 protocol.
The randomisation has been performed in RandAll using an appropriate block size.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
4.2.
Final Analysis
5.
Approximately 1200 subjects will be screened to achieve 594 evaluable subjects (with at
least one pre-dose or 23-24 hour post-dose FEV1 assessment on or after nominal Day 7)
or 99 subjects per group.
This sample size is based on the primary endpoint of change from baseline in trough
FEV1 and has 97% power to detect a slope of 4ml/mcg (a dose response effect of 200ml
improvement in FEV1 per 50mcg of GW642444M). This assumes a standard deviation of
430ml (based on previous studies) and significance declared at the two-sided 5% level.
Similarly, there is >99 % power to detect slopes of 8ml/mcg (200ml improvement per
25mcg dose), 16 ml/mcg (200 ml improvement per 12.5 mcg dose) and 32 ml/mcg (200
ml improvement per 6.25mcg dose). The 3mcg dose is assumed to be a non-effective
dose and the study has approximately 96% power to detect a 200ml effect between this
dose and the 50mcg dose, excluding placebo from the dose response analysis.
Additionally, the study has 90% power to detect a difference of 200ml in pairwise
comparisons of change from baseline in trough FEV1 between any active dose and
placebo.
Any subject whose FEV1 measurement at Day 28 is missing will be included in the
analysis of the primary endpoint by imputation using the preceding non-missing FEV1
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value (Last Observation Carried Forward [LOCF]). Similarly, subjects whose FEV1
measurement is missing at Day 28 will be included in a sensitivity analysis of the primary
endpoint by using information obtained from FEV1 measurements at earlier time points in
a Repeated Measures analysis.
No sample size review is planned or will be conducted for this study.
5.1.
The assumption of a standard deviation of 430ml in trough FEV1 is based on data from
previous studies. The mean of the 23 and 24 hour post-dose assessments will be used to
derive the primary endpoint which is likely to reduce variability further. However, if the
actual standard deviation in this study differs from 430ml, then Table 2 demonstrates the
power for both the dose response test and the pairwise comparisons with the proposed
sample size of 99 subjects per group.
Table 2
Standard Deviation
(ml)
400
415
430
440
450
460
6.
ANALYSIS POPULATIONS
6.1.
Total Population
This population will comprise all subjects screened and for whom a record exists on the
study database and will be used for the tabulation of reasons for withdrawal before
randomisation.
6.2.
The ITT Population will comprise all subjects randomised to treatment and who have
received at least one dose of trial medication. Randomised subjects will be assumed to
have received trial medication unless definitive evidence to the contrary exists. This will
constitute the primary population for all analyses of efficacy and safety measures.
6.3.
The PP Population will consist of all subjects in the ITT Population who do not have any
full protocol deviations. Protocol deviations can be either full or partial. Subjects with
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only partial deviations will be considered part of the PP Population but from the date of
their deviation onwards, their data will be excluded.
The decision to exclude a subject or part of their data from the PP Population will be
made prior to breaking the blind. Protocol deviations that will lead to full or partial
exclusion from the PP population are detailed in Section 10.2 (Protocol Deviations). This
population will be used for confirmatory analyses of the primary efficacy endpoint only.
7.
TREATMENT COMPARISONS
7.1.
Primary Comparisons
The primary treatment comparison is a test for linear dose response in trough (prebronchodilator and pre-dose) PM FEV1 derived from the mean of the 23 and 24 hour
post-dose assessments at Day 28 across the five doses of GW642444M and placebo in
order to demonstrate overall efficacy of GW642444M. If this test is statistically
significant, each dose of GW642444M will be compared with placebo to identify
effective doses. These comparisons will be performed by the use of hypothesis tests as
described in Section 2.3. These comparisons are to be performed using the ITT
Population using Analysis of Covariance (ANCOVA) with LOCF to impute missing data.
A supporting analysis will also be performed using a Repeated Measures Mixed Model.
Missing data are not implicitly imputed in this analysis. However, all non-missing data
for a subject will be used within the analysis to estimate the Day 28 treatment effects.
A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance
level) is considered acceptable for this study. Since the pairwise comparisons with
placebo will only be performed if GW642444M is first shown to be efficacious relative to
placebo by means of the primary dose-response test, no further multiplicity adjustments
will be applied.
7.2.
The primary comparisons will be supported by the same tests performed using the PP
Population (i.e. pairwise comparisons will be performed using the PP population only if
they are performed for the ITT population). They will also be supported by the same tests
performed using a Repeated Measures Mixed Model on the ITT population. Missing data
are not implicitly imputed in this analysis; however, all non-missing data for a subject
will be used within the analysis to estimate the day 28 treatment effects.
The dose response across the five active doses of GW642444M will be explored on the
ITT population excluding placebo from the analysis.
Pairwise comparisons will be performed for the other key efficacy endpoints on the ITT
population.
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7.3.
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In the data displays the randomised treatments will be identified and ordered as shown in
Table 3:
Table 3
Treatment Group
Descriptor
8.
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
All programming will be performed in a HARP environment using SAS Version 8.2 or a
later release.
At a minimum, the following basic descriptive statistics will be used in the summary
tables for continuous variables:
Table 4
Label
Description
N
n
Mean
SD
Median
Min.
Max.
Always present to 0 dp
Always present to 0 dp
1 dp more
2 dp more
1 dp more
Same as data
Same as data
In general, the following variables will be used in the presentation of results from
statistical analysis (unless otherwise stated):
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Table 5
Label
Description
Estimate of
Slope
LS Mean
LS Mean
Change
Std Err
Difference
95% CI
p-value
8.1.
2 dp more
1 dp more
1 dp more
Always present to 3 dp
(or <0.001 or >0.999)
Multicentre Studies
It is anticipated that approximately 100 centres (worldwide) will participate in the study.
Therefore, it is likely that many centres will enroll very small numbers of subjects.
Consequently, all centres within the same country will be pooled. If any country has less
than 12 subjects in total then it will be pooled with another country within a similar
geographical region and these amalgamations will be used whenever country is included
in the analysis. All amalgamations will be finalised and documented prior to unblinding
the treatment codes. All summaries and analyses will be of all countries combined
(analysis models will include country as a covariate).
8.2.
Unless otherwise stated in Section 11 or Section 12, all models used for the efficacy and
safety analyses will be adjusted for baseline value, country, sex, age, baseline percent
predicted FEV1 stratum and treatment group. Any stratum by treatment interaction will
be explored as part of the model checking process.
Baseline values are defined in Section 9.2.1.
8.3.
Examination of Subgroups
8.4.
There is a single primary endpoint in this study which is the mean change from baseline
at the end of the 28-day treatment period in trough (PM pre-bronchodilator and pre-dose)
FEV1 derived from the mean of the 23 and 24 hour post-dose assessments.
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Since the pairwise comparisons with placebo will only be performed if GW642444M is
first shown to be efficacious relative to placebo by means of the primary dose-response
test, no further multiplicity adjustments will be applied.
8.5.
Statistical Models
Appropriate graphs will be reviewed as part of the model checking process to ensure that
distributional assumptions hold. Interactions with treatment will be explored for all
covariates and tests for interactions will be at the 10% significance level. Any significant
interactions that are found will be thoroughly investigated and where necessary, extra
outputs will be produced.
9.
9.1.
Where possible, data from subjects who withdraw prematurely from the study will be
included in any analyses. In general, the minimum data required will be a baseline
evaluation and at least one post-baseline evaluation.
9.1.1.
Primary Endpoint
Missing trough FEV1 data at Day 28 will be imputed for the primary analysis using last
observation carried forward (LOCF). This means that where the endpoint is missing the
last valid non-missing post-baseline trough assessment will be used instead. Only
measurements from scheduled visits will be used. The exposure treatment start and stop
dates will be used to determine whether a measurement was on-treatment and where
these are missing, all measurements will be assumed to be on-treatment.
For the primary endpoint, trough FEV1 will be derived using the mean of the 23 and 24
hour post-dose FEV1 assessments. If either the 23 or 24 hour post-dose FEV1
assessments on Day 28 is missing, the non-missing of the two values will be used as the
primary endpoint. If both the 23 and 24 hour assessments are missing on Day 28, the
pre-dose Day 28 assessment will be used as the endpoint value. If the Day 28 pre-dose
assessment is also missing then the Day 14 pre-dose assessment will be used as the
endpoint value. If the Day 14 pre-dose assessment is also missing then the Day 7 predose assessment will be used as the endpoint value. If the Day 7 pre-dose assessment is
missing then the endpoint will be set to missing.
The primary endpoint will also be analysed using Repeated Measures whereby missing
data are not directly imputed but the correlation between visits for all subjects is used to
adjust the estimate of treatment effect. All of the available FEV1 measurements from the
scheduled visits will be used in this analysis.
For the Per Protocol analysis, the time of the FEV1 measurements must be within 30
minutes of the planned time relative to dosing for 23-24 hour assessments, or within 1
hour of the time of the corresponding baseline measurement for pre-dose assessments.
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Any FEV1 measurements outside of this time window will be considered missing (note
that the measurements will be considered missing for the sake of the Per Protocol
analysis, but the subject will not be considered a protocol deviator). Similarly any FEV1
measurements that are taken within 6 hours after the use of rescue medication will be
considered missing (note: this only applies to 23-24 hour or pre-dose assessments that
would otherwise be eligible to be included in the analysis of the primary endpoint).
Subjects with only partial protocol deviations will have any data prior to their date of
deviation included in the primary analysis.
9.1.2.
Secondary efficacy endpoints relating to daily diary assessments will be calculated from
all available data over the period of interest - no imputations will be performed on
missing daily diary data. Weekly means and other time periods will be considered
missing if less than 2 days (i.e., 24-hr periods) are recorded.
For analyses of symptoms and rescue use over 24-hour periods, each 24-hour period
incorporates a morning and evening assessment from the same day. A 24-hour period will
be considered symptom-free only if the subjects responses to both morning and evening
assessments indicate no symptoms. Similarly, for rescue use a 24-hour period will be
considered rescue use-free only if the subjects responses to both morning and evening
assessments indicate no use of rescue medication. Data for a 24-hour period will be
considered as missing if both daytime and night time responses are missing. Data will
also be considered missing if one of the daytime or night time responses is missing and
the other response is zero. Table 6 and Table 7 provide examples of how missing data
will be handled.
Table 6
Example
Symptom Scores
1
2
3
4
5
AM
PM
1
0
2
Missing
Missing
0
0
Missing
0
Missing
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Table 7
Example
1
2
3
4
5
9.1.3.
AM
PM
3
0
5
Missing
Missing
0
0
Missing
0
Missing
Any missing data in the analyses of the remaining secondary and safety endpoints will
remain missing in the analyses.
9.2.
9.2.1.
The baseline values for each clinic assessment endpoint will be the Visit 2 pre-dose
assessment. An exception will be the baseline value for the FEV1 response to
salbutamol/albuterol, which will be the Screening pre-salbutamol assessment. The
baseline value for vital signs, ECG, and potassium and glucose analyses will be the Visit
2 pre-dose assessment. For vital signs and ECG, if the Visit 2 pre-dose assessment is
missing then the screening value will be used in its place. For laboratory assessments the
screening measurements will be used as baseline. The baseline values for the symptom,
rescue-use and PEF related endpoints will be derived from the last 7 days of the Daily
Diary prior to the randomisation of the subject.
Change from baseline will be defined as the difference between the value of the endpoint
at the time point of interest and the baseline value as defined above.
9.2.2.
For FEV1 (0-4hr) on Days 1 and 28, systolic blood pressure, pulse rate, QTc(B), QTc(F)
and glucose, the maximum change from baseline is defined by ordering all the change
from baseline values and selecting the positive value with the greatest magnitude. If there
are no positive values the negative value with the smallest magnitude will be selected.
For diastolic blood pressure and potassium the minimum change from baseline is defined
by ordering all the change baseline values and selecting the lowest negative value. If
there are no negative values the positive value with the smallest magnitude will be
selected.
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9.2.3.
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For endpoints analysed as weighted mean change from baseline, this will be calculated
using the average area under the curve minus baseline (AAUCMB), calculated using the
trapezoidal rule, and dividing by the relevant time interval.
Actual times will be used for the calculation. Pre-dose will be counted as the 0 hr
(baseline) observation in the calculation of the AAUCMB. Allowable time windows for
the calculation of AUC are as follows:
For 0-4 hour endpoints, measurements up to 5 hours (actual time) will be included
For 0-24 hour endpoints, measurements up to 25 hours (actual time) will be included.
The AAUCMB will only be calculated if at there are at least the following non-missing
values in the time period of interest:
For 0-4 hour endpoints, 0 hour (baseline) and a measurement between 3 hours and 5
hours (actual time), and,
For 0-24 hour endpoints, 0 hour (baseline) and at least one post-dose measurement
between 0 and 5 hours (actual time), and at least one measurement between 15 and
21 hours (actual time), and at least one measurement between 22.5 and 25 hours
(actual time).
If these values are missing then the AAUCMB will not be calculated, and the endpoint
treated as missing.
The AAUCMB will be calculated from first non-missing time point to the last nonmissing time point. If one or more observations are missing between two non-missing
observations, the value(s) will be linearly interpolated between the two non-missing
values.
The AAUCMB( t0 tL hrs) will be calculated as follows:
1
AAUCMB( t0 tL hrs) =
2
i=0
(C i + C i +1 )(t i +1 t i )
t L t0
CB
Where,
i = collected measurement
L = last collected measurement
Ci = result of collected measurement i
CB = Baseline
ti = actual time of assessment for collected measurement i
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Trough FEV1 at Visit 2/2A will be derived using the mean of the 23 and 24 hour postdose FEV1 assessments on Day 1. If either the 23 or 24 hour post-dose FEV1
assessments on Day 1 is missing, the non-missing of the two values will be used. Trough
FEV1 at Visit 3 will be the pre-dose assessment on Day 7 and the trough FEV1 at Visit 4
will be the pre-dose assessment on Day 14. Missing values will not be imputed.
9.2.5.
Peak post-dose FEV1 (0-4 hrs) on Day 28 is taken as the maximum post-dose FEV1
recorded over the nominal time points of 15 and 30 minutes, 1, 2, 3, and 4 hours. It will
only be calculated if there is at least one non-missing FEV1 value recorded within the
first hour of dosing. If this is not the case it will be considered missing.
Peak to trough FEV1 ratio on Day 28 is defined as the peak post-dose FEV1 (0-4 hrs) as
defined above, divided by the trough FEV1, for Day 28. The trough FEV1 as used in the
ratio is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on
Day 28, with no imputation.
9.3.
Assessment Windows
As explained in Section 9.1.1, only FEV1 measurements that are within 30 minutes of
the time of the planned time relative to dosing for 23-24 hour assessments, or within 1
hour of the time of the corresponding baseline measurement for pre-dose assessments
will be included in the Per Protocol analysis of the primary endpoint. Any FEV1
measurements outside of this time window will be considered missing from the Per
Protocol analysis (note that the measurements will be considered missing for the sake of
the Per Protocol analysis, but the subject will not be considered a protocol deviator).
9.4.
Haematological and clinical chemistry data from subjects who have values outside the
normal range will be listed. Plots of liver function test results will be produced and
annotated with the clinical concern levels which are 2 times the upper limit of normal for
ALT, AST and Alkaline Phosphatase and 1.5 times the upper limit of normal for Total
Bilirubin. Plots of minimum potassium and maximum glucose will be produced and
annotated with the clinical concern levels which are 0.9 times the lower limit of normal
for potassium and 1.5 times the upper limit of normal for glucose.
9.5.
Mis-Stratification
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10.
STUDY POPULATION
10.1.
Disposition of Subjects
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The number of subjects in each analysis population will be presented (Table 6.1) and the
total number of subjects attending each clinic visit will also be summarised by treatment
group (Table 6.4).
A summary of the number and percentage of subjects who completed the study as well as
subjects who withdrew prematurely from the study will be presented for each treatment
group along with the primary reason for withdrawal and any sub reasons both prior to and
post randomisation (Table 6.2 and Table 6.3). Reasons for premature withdrawal will be
presented in the order they are displayed in the eCRF. A Kaplan-Meier plot showing the
percentage of subjects remaining in the study over time will be produced (Figure 6.1) as
well as a plot showing subject withdrawals due to lack of efficacy over time (Figure 6.2).
A listing of the subject disposition/end of study record for all subjects who discontinued
the study prematurely will be produced (Listing 6.1).
A summary of the number of subjects by centre (Table 6.5) and a listing of the
randomisation data (Listing 6.6) will also be produced.
10.2.
Protocol Deviations
The number and percentage of subjects who were randomised or entered into the trial, but
deviated from the inclusion or exclusion criteria, will be summarised (Table 6.6). A
listing of the inclusion/exclusion criteria deviation record for all subjects with deviations
will be produced (Listing 6.2).
A summary showing the number of subjects within each treatment group with full and
partial protocol deviations will be presented (Table 6.7). A by-subject listing of reasons
for exclusion from the Per Protocol population will also be produced (Listing 6.7).
Reasons for protocol deviations include the following:
1.
2.
3.
Remaining in the study after being ineligible for the study based on the lack of
efficacy withdrawal criteria as described in Section 4.5 of the protocol.
4.
Treatment Compliance of < 80%. (The protocol required subjects to take their study
medication every evening each day. For reporting and analysis purposes, treatment
compliance of 80% is defined here as a lower limit for subjects to remain in the Per
Protocol population.)
5.
Taking the wrong study treatment at any time during the study.
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Apart from any treatment deviations, all full and partial protocol deviations will be
agreed upon prior to unblinding the study.
In addition only FEV1 measurements that are within 30 minutes of the planned time
relative to dosing for 23-24 hour assessments, or within 1 hour of the time of the
corresponding baseline measurement for pre-dose assessments will be included in the Per
Protocol analysis of the primary endpoint. Any FEV1 measurements outside of this time
window will be considered missing (note that the measurements will be considered
missing for the sake of the Per Protocol analysis, but the subject will not be considered a
protocol deviator). Similarly any FEV1 measurements that are taken within 6 hours after
the use of rescue medication will be considered missing for the Per Protocol analysis
(note: this only applies to 23-24 hour or pre-dose assessments that would otherwise be
eligible to be included in the analysis of the primary endpoint).
A listing of subjects for whom the treatment blind was broken during the study will be
produced (Listing 6.3). A listing giving details of any treatment misallocations will also
be produced (Listing 6.8).
10.3.
10.3.1.
Demographic characteristics (age, ethnicity, sex, height and weight) will be summarised
for the Intent-to-Treat population (Table 6.8) and the Per Protocol population (Table 6.9).
Demographic characteristics will also be listed (Listing 6.4). Age will be calculated from
the date of birth and the date of screening (Visit 1).
The five high level FDA race categories and designated Asian subcategories will be
summarised (Table 6.10) along with all combinations of high level categories which exist
in the data. All five of the high level race categories and the two Asian subcategories
must appear on the display even if there are no subjects in a particular category, but
combinations that do not exist in the data do not need to be represented.
The high level FDA race categories and designated Asian subcategories are:
1. African American/African Heritage
2. American Indian or Alaska Native
3. Asian
a. Central/South Asian Heritage
b. Japanese/East Asian Heritage/South East Asian Heritage
c. Mixed Asian Heritage (only required if data exists)
4. Native Hawaiian or other Pacific Islander
5. White
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Combinations will be represented as the concatenation of the high level category terms,
e.g., White & Asian. The designated Asian subcategories will not be summarised as
combinations with other categories.
A subject will only be represented in a single category. A subject who selects a
combination of races will be counted in the combination of terms, not in each of the
constituent terms. Therefore the counts will add up to the total number of subjects with a
response, and the percentages will add to 100%.
The twelve standard race categories collected on the IDSL eCRF page will be
summarised (Table 6.11) along with categories for mixed race.
The twelve standard race categories and mixed race categories are:
1.
2.
3.
4.
5.
6.
7.
8.
9.
History of tobacco use is captured at screening and will be summarised (Table 6.12) and
listed (Listing 6.9).
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History of asthma including duration of asthma and history of atopy will also be
summarised (Table 6.13) and listed (Listing 6.10).
10.3.3.
Medical Conditions
A summary of the number and percentage of subjects who report current medical
conditions will be produced (Table 6.14). A by-subject listing will also be produced
(Listing 6.11).
10.3.4.
Concomitant Medications
Concomitant medications will be coded using the GSK Drug coding dictionary, an
internal validated medication dictionary. A summary of the number and percentage of
subjects with concomitant medications will be displayed using a method which presents
multi-ingredient medications according to their combination ATC classification rather
than the classifications of the ingredients. This display will also include single-ingredient
medications. Summaries will be split into asthma and non-asthma concomitant
medications, as well as into those taken pre-, during, and post-treatment (Table 6.15 to
Table 6.20). Asthma concomitant medications will be displayed without regard to ATC
classification.
A medication will be summarised in every period (pre/during/post) in which it was taken,
so a medication that was started in the run-in and stopped during active treatment will
appear in both the pre-treatment and the during treatment tables.
During treatment will be considered to be from the day after the treatment start date until
the treatment stop date.
The methods for dealing with partial drug start and stop dates will be the same for all
medications and will be to include each drug in every period in which it could
conceivably have been taken. For example, if we only have month and year for the drug
start date and it is the same as the month and year of the treatment start date, then the
drug will be considered to have started pre-treatment. Similarly if we only have the year
that the drug was stopped and it is the same as the year that the treatment was stopped
then the drug will be considered to have stopped post-treatment.
A listing of the relationship between ATC level 1, ingredient and verbatim term will be
produced (Listing 6.13) along with a listing of all concomitant medications recorded
(Listing 6.12).
10.3.5.
The following lung function test results taken at visit 1 (screening) will be summarised
(Table 6.21):
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Treatment Compliance
Percentage treatment compliance will be calculated for each subject based on the total
number of inhalations taken from the Novel Dry Powder Inhaler and the expected
number of inhalations to be taken. The expected number of inhalations will be derived as
the expected number of inhalations per day multiplied by the number of days on study
drug based on the subjects treatment start and stop date for the device.
Thus, treatment compliance will be derived as:
(
Stop
_
Date
Start
_
Date
+
1
Where Expected _ Inhalations is equal to 1 and Start _ Date and Stop _ Date are the
dates of the first and last doses of study drug, respectively.
The total number of inhalations taken will be based on the dose counter. If there is no
dose counter information at all then the compliance will be missing.
Percentage treatment compliance will be summarised (Table 6.22).
11.
EFFICACY ANALYSES
11.1.
The primary endpoint of mean change from baseline at Day 28 in trough (PM prebronchodilator and pre-dose) FEV1 will be derived from the mean of the 23 and 24 hour
post-dose assessments and missing data will be imputed using LOCF as described in
Section 9.1.1 and summarised (Table 7.1). The primary analysis will be performed using
an ANCOVA model on the Day 28 data with effects due to baseline FEV1, centre
grouping (country), age, sex, baseline percent predicted FEV1 stratum and dose/treatment
group.
A linear trend contrast will be constructed using the Day 28 data to evaluate the dose
response trend using a SAS procedure with the following syntax:
proc mixed data=start ;
class sex country stratum;
model FEV1 = dose sex country age baseline stratum / ddfm=kr s cl ;
ods output SolutionF=sol ;
run ;
quit ;
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where dose is the dose in mcg for the GW642444M groups and 0 for the Placebo group.
The estimate of slope for the dose term, 95% confidence interval and p-value will be
presented (Table 7.2). This will also be repeated excluding the Placebo group to
investigate the dose response across the five active doses of GW642444M (Table 7.3).
If the primary dose response test is significant (p-value0.05) then estimated treatment
differences for all pairwise comparisons will be presented together with 95% confidence
intervals for the difference and p-values for Day 28 (Table 7.4). This will be
accomplished by using a SAS procedure with the following syntax:
proc mixed data=start ;
class trtcd sex country stratum;
model FEV1 = trtcd sex country age baseline stratum / ddfm=kr ;
lsmeans trtcd / cl diff om;
ods output lsmeans=lsmeans ;
ods output diffs=diffs ;
run ;
quit ;
If the primary dose response test is significant then the following two figures will be
produced. The pairwise treatment differences will be plotted along with the
corresponding 95% confidence intervals (Figure 7.1). The adjusted means for all
treatments will be plotted and a linear regression line overlaid (Figure 7.2). The
regression line is for illustrative purposes only and will be based on the adjusted means of
the Placebo and GW642444M treatment groups. Thus if the number of subjects differ
between the treatment groups the slope may differ slightly from that derived in the
primary dose response test.
A box plot and plot of the cumulative distribution of the change from baseline in trough
FEV1 derived using LOCF will be produced regardless of whether the primary dose
response test is significant (Figure 7.3 and Figure 7.4).
The summary statistics, linear trend test with Placebo, pairwise comparisons and figures
for trough FEV1 derived using LOCF will be repeated on the Per Protocol population
(Table 7.5, Table 7.6, Table 7.7, Figure 7.5, Figure 7.6, Figure 7.7, and Figure 7.8). Note
the analysis without placebo will not be repeated.
The dose response test with placebo for Day 28 will also be performed in a sensitivity
analysis using a repeated measures model which will include data from Day 7 (pre-dose
assessment), Day 14 (pre-dose assessment), and Day 28 (pre-dose assessment, 23 and 24
hour post-dose assessment). The dose response model will allow for effects due to
baseline trough FEV1, centre grouping (country), age, sex, baseline percent predicted
FEV1 stratum and dose (Table 7.8). This model will also contain a visit-by-dose
interaction term. Note the dose-response analysis without placebo will not be repeated.
The pairwise comparisons analysis for Day 28 will be modelled as described for the dose
response test and will allow for effects due to baseline trough FEV1, centre grouping
(country), age, sex, baseline percent predicted FEV1 stratum and treatment group (Table
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7.9). This model will also contain a visit-by-treatment interaction term. This model will
include the following data points: pre-dose Day 7 ("visit 3"), pre-dose Day 14 ("visit 4"),
pre-dose Day 28 ("visit 5"), and trough Day 28 (mean of the 23 and 24 hour post-dose
assessments) ("visit 5A"). The pairwise comparisons at each of these days will all be
displayed and the adjusted means and 95% confidence intervals for these days will be
plotted (Figure 7.9). Treatment differences from placebo will also be plotted (Figure
7.10). The dose response test and pairwise comparisons will use SAS procedures with
the following respective syntaxes:
proc mixed data=start ;
class sex country stratum visit subjid ;
model FEV1 = dose sex country age baseline stratum
visit visit*baseline visit*dose / ddfm=kr ;
repeated visit / subject=subjid type=un;
estimate 'Day 28' dose 1 visit*dose 0 0 0 0.5 0.5 / cl ;
ods output estimates=est ;
run ;
quit ;
Note that the intention of the estimate statement is to obtain the estimate of the mean
response of 23 and 24 hours on Day 28.
proc mixed data=start ;
class trtcd sex country stratum visit subjid ;
model FEV1 = trtcd sex country age baseline stratum
visit visit*baseline visit*trtcd / ddfm=kr ;
repeated visit / subject=subjid type=un ;
lsmeans visit*trtcd / cl diff e om=OMdset at (baseline age)=(&blm. &agem.);
ods output lsmeans=lsmeans ;
ods output diffs=diffs ;
run ;
quit ;
Where OMdset is a dataset with a row for every visit-subject combination that contains
all of the covariates and blm and agem are macro variables containing the means for
baseline and age for the subjects used in the analysis. These are used to derive the
adjusted means using coefficients which are based on the subjects used in the analysis.
The pairwise comparisons for the Per Protocol and repeated measures analysis will only
be produced if primary LOCF dose response test on the ITT population is significant, i.e.
Table 7.7, Table 7.9, Figure 7.5, Figure 7.6 and Figure 7.9 will only be produced if Table
7.4 is produced.
Raw FEV1 and change from baseline values will also be summarised for all treatments at
all visits for pre-dose and 23-24 hour post-dose time points (Table 7.10). All FEV1 data
will be listed (Listing 7.1)
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11.2.
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The change from baseline in trough (23 and 24 hour post-dose assessments) FEV1 at the
end of treatment will be analysed for each percent predicted FEV1 strata separately in
order to investigate the consistency of the dose response relationship for the different
disease severities. An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, and dose will be used to estimate the dose response slope presented
together with 95% confidence intervals for each baseline percent predicted FEV1 stratum
(Table 7.12). An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, stratum, treatment group, and treatment group by stratum interaction
will be used to estimate the treatment differences for all pairwise comparisons for each
stratum, which will be presented together with 95% confidence intervals (Table 7.13,
Figure 7.11). The adjusted means for all treatments will be plotted and a linear
regression line overlaid for each stratum (Figure 7.12). We are using the interaction
between treatment group and stratum to estimate the treatment effect for each stratum
because this study is not powered for subgroup analyses. Statistical significance testing
will not be performed for the strata analyses. Summary statistics will also be presented
for each stratum (Table 7.11). The as-randomised strata and actual strata will be
summarised (Table 6.23). Summaries of percent predicted FEV1 at Day 1 pre-dose will
be presented by actual stratum (Table 6.24).
11.2.2.
The 24-hour serial FEV1 will be measured on Days 1 and 28 at the following time points;
pre-dose, and 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours postdose. The 6 and 12 hour time points will only be measured in a subgroup of subjects. The
change from baseline in weighted mean for 24-hour serial FEV1 on Days 1 and 28 will be
compared for each GW642444M group versus placebo using an ANCOVA model with
effects due to baseline (pre-dose measurement on Day 1), centre grouping, age, sex,
baseline percent predicted FEV1 stratum and treatment group. This analysis will include
all ITT population subjects, including those with the additional time point measurements
at 6 and 12 hours after dosing. The weighted mean values will include the 6 and 12 hour
data for those subjects with these assessments. Estimated treatment differences for all
comparisons of GW642444M with placebo will be presented and plotted together with 95
% CIs for the difference and p-values (Table 7.18 and Figure 7.13). The summary
statistics will also be presented for the raw serial measurements for 0-24 hours and for the
weighted means (Table 7.14 and Table 7.17). The summary statistics will also be
presented for the absolute and percentage change from baseline in serial FEV1 for 0-4
hours (Table 7.15 and Table 7.16).
Additionally, a sensitivity analysis will be performed to assess the impact of the 6-12
hour time points. The same ANCOVA model as described above for 0-24 hr weighted
mean FEV1 will be run in three additional ways:
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Subset of subjects who had the 6-12 hr time points measured. All time points
will be included
Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time
points will be excluded
For each of these subject groups, estimated treatment differences for all comparisons of
GW642444M with placebo will be presented and plotted together with 95 % CIs for the
difference and p-values (Table 7.19, Table 7.20, Table 7.21 and Figure 7.14).
A further sensitivity analysis will be performed to assess the impact of rescue medication
on the weighted mean 24 hour serial FEV1. The same ANCOVA model as described
above for 0-24 hr weighted mean FEV1 will be run after removing the FEV1
measurements that were taken within 6 hours after rescue medication use (Table 7.22).
Plots of mean FEV1 over time will be provided for both Day 1 and Day 28, with 95%
confidence intervals at the 0, 4, 16 and 24 hour time points (Figure 7.15). Plots of the
mean absolute and percentage change from baseline in FEV1 for 0-4 hours will be
provided for both Days 1 and 28 (Figure 7.16 and Figure 7.17).
11.2.3.
The change from baseline in daily trough (pre-dose and pre-rescue bronchodilator) PM
PEF averaged over the 28-day treatment period will be compared for each GW642444M
dose versus placebo using an ANCOVA model with effects due to baseline PM PEF,
centre grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
stimated treatment differences for all comparisons will be presented together with 95%
confidence intervals for the difference and p-values (Table 7.38). Summary statistics will
also be presented (Table 7.31).
In addition summary statistics for the change from baseline in PM PEF over the first 14
days on study treatment and over Weeks 1, 2, 3, 4, endpoint and follow-up will be
presented alongside. A plot showing the mean change from baseline at each day will also
be produced (Figure 7.22).
PEF averaged over the 28 day treatment period will use all available data up to and
including Day 28. Endpoint will be defined as the last 7 days on study medication ending
with the treatment stop date. If the treatment stop date is missing then the date of the last
clinic visit will be used instead. Follow-up will be defined as the 7 days after treatment,
ending with the follow-up visit. Again, if the treatment stop date is missing then the date
of the last clinic visit will be used instead. All other time periods will be exactly as
described, irrespective of when clinic visits occurred e.g. Week 1 will include the first 7
days after randomisation regardless of when visit 3 occurred.
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11.2.4.
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Morning PEF
The change from baseline in daily AM PEF averaged over the 28-day treatment period
will be summarised and analysed as described for Evening Trough PEF (Table 7.39,
Table 7.40 and Figure 7.23).
11.2.5.
The change from baseline in the percentage of symptom-free 24-hour periods and rescuefree 24-hour periods over the 28-day treatment period will be calculated for each subject.
Comparisons will then be made of each GW642444M dose versus placebo using an
ANCOVA model with effects due to baseline value, centre grouping, age, sex, baseline
percent predicted FEV1 stratum and treatment group. Estimated treatment differences for
all comparisons will be presented together with 95% confidence intervals for the
difference and p-values (Table 7.42 and Table 7.44). Summary statistics will also be
presented (Table 7.41 and Table 7.43).
If the failure of distributional assumptions prevents the use of an ANCOVA model then
the data will be split into appropriate categories and a proportional odds logistic
regression analysis will be used instead. The categories will be agreed and documented
prior to unblinding.
11.2.6.
Response to salbutamol/albuterol
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GW642444M group versus placebo using an ANCOVA model as described above for the
change between Day 1 and Day 28. Estimated treatment differences for all comparisons
will be presented together with 95% CIs for the difference and p-values (Table 7.25 and
Figure 7.20).
Baseline in this analysis is the pre-salbutamol FEV1 value taken at screening.
11.3.
11.3.1.
The maximum increase and weighted mean change in FEV1 (0-4hr) on Days 1 and 28
compared with baseline will be calculated for each subject. Comparisons will then be
made of each GW642444M dose versus placebo using an ANCOVA model with effects
due to baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum
and treatment group. Estimated treatment differences for all comparisons will be
presented together with 95% confidence intervals for the difference and p-values (Table
7.27 and Table 7.28). Summary statistics will also be presented (Table 7.26 and Table
7.29).
The proportion and cumulative proportion of subjects obtaining both 200mL and
12% increase from baseline in FEV1 (0-4hr) at each planned time point on Days 1 and 28
will be summarised (Table 7.28 and Table 7.31). The proportion and cumulative
proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4hr) at each
planned time point on Days 1 and 28 will be summarised (Table 7.32 and Table 7.33).
Peak post-dose FEV1 (0-4 hrs) on Day 28 will be summarised (Table 7.34) and analysed
as described above for maximum increase in FEV1 (0-4hr) (Table 7.35 and Figure 7.21).
Peak to trough FEV1 ratio on Day 28 will be summarised (Table 7.36).
11.3.2.
The mean change from baseline in the percentage of symptom-free days, symptom-free
nights, rescue-free days and rescue-free nights over the 28 day treatment period will be
calculated for each subject. Comparisons will then be made of each GW642444M dose
versus placebo using an ANCOVA model with effects due to baseline value, centre
grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Estimated treatment differences for all comparisons will be presented together with 95%
confidence intervals for the difference and p-values (Table 7.46, Table 7.48, Table 7.50
and Table 7.52). Summary statistics will also be presented (Table 7.45, Table 7.47, Table
7.49 and Table 7.51). All available data up to and including the last clinic visit will be
utilised.
If the failure of distributional assumptions prevents the use of an ANCOVA model then
the data will be split into appropriate categories and a proportional odds logistic
regression analysis will be used instead. The categories will be agreed and documented
prior to unblinding.
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Fishers Exact test will be used to compare the number of withdrawals due to lack of
efficacy between each GW642444M treatment group versus placebo (Table 7.53). (See
Section 10.1 for subject disposition tables, listings and figures).
12.
SAFETY ANALYSES
12.1.
Extent of Exposure
The number of days on study drug for each subject will be summarised (Table 8.1) and
will be calculated as (date of last dose date of first dose) + 1. A listing of exposure and
compliance data will also be produced (Listing 8.1).
12.2.
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary, to give a preferred term and a system organ class. The
verbatim text will be presented in the listings. AEs will be classified as pre-treatment, ontreatment and post-treatment by comparing the start date of the AE to the dates of the first
and last doses of study medication using the following definitions:
Where AE onset dates are missing or partial than the AE will be considered on-treatment
unless there is evidence to the contrary (e.g. the month of the start date is present and is
less than the month of the first dose of study medication).
The number and percentage of subjects with all adverse events (regardless of causality)
will be summarised for each treatment, sorted by system organ class, preferred term and
total incidence. System organ class will not be presented when the overall incidence for
any adverse event within the particular system is 0. If the total incidence for any two or
more adverse events is equal, the events will be presented in alphabetical order. This will
be done separately for on-treatment and post-treatment AEs (Table 8.2 and Table 8.3). A
further summary of on-treatment adverse events with a total incidence of greater than or
equal to 3% will be produced (Table 8.4).
A summary of any drug related (as recorded by the Investigator) AEs (Table 8.5) and a
summary of any AEs leading to permanent discontinuation of study drug or withdrawal
from the study (Table 8.6) will also be produced.
Summaries of all serious AEs will be produced separately for pre, on and post-treatment
AEs (Table 8.7, Table 8.8 and Table 8.9).
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The association between the adverse event system organ class, preferred terms and the
verbatim text will be also be summarised (Table 8.10).
A listing will be produced of subject numbers for each adverse event (Listing 8.2).
Pre, on and post-treatment adverse events will be listed, sorted by treatment, subject,
onset date and onset time (Listing 8.3, Listing 8.4 and Listing 8.5). In addition listings
will be produced for all AEs leading to permanent discontinuation of study drug or
withdrawal from the study (Listing 8.6), for all non-fatal serious AEs (Listing 8.7) and
for all fatal AEs (Listing 8.8). A listing will also be produced of AEs for subjects not in
the ITT population (Listing 8.9). Adverse events will not be summarised by maximum
severity, which is a change from what is stated in the protocol.
12.3.
Summary tables and listings will be provided for serious and fatal adverse events (See
Section 12.2). In addition, all deaths and serious AE's will be documented in a case
narrative format in the clinical study report.
12.4.
12.5.
Any pregnancies reported during the study will be summarised in case narratives.
Pregnancy complications and elective terminations for medical reasons must be reported
as an AE or SAE.
12.6.
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Urinalysis dipstick results will be summarised by treatment (Table 8.17) and listed
(Listing 8.12) at each planned time point when they are collected.
12.7.
12.7.1.
Summary statistics of systolic and diastolic blood pressure and pulse rate will be
presented for each treatment group at each time point (Table 8.18). This will be repeated
using the change from baseline values (Table 8.19). All vital signs data will be listed
(Listing 8.13).
Additionally, the following vital signs endpoints will be derived on Days 1, 7, 14 and 28:
Derived Endpoint
Change from baseline in maximum value (0-4 hours)
Change from baseline in minimum value (0-4 hours)
Weighted mean change from baseline (0-4 hours)
Measure(s)
systolic blood pressure
pulse rate
diastolic blood pressure
blood pressure
pulse rate
They will be summarised in Table 8.20, Table 8.23, Table 8.26, Table 8.29, Table 8.32,
and Table 8.35, and will be analysed using ANCOVA with effects due to baseline value,
centre grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Pairwise comparisons of each treatment group versus placebo will be performed and
treatment differences will be presented with 95% confidence intervals (Table 8.22, Table
8.25, Table 8.28, Table 8.31, Table 8.34, and Table 8.37). In addition, change from predose will be summarised in Table 8.21, Table 8.24, Table 8.27, Table 8.30, Table 8.33,
and Table 8.36.
A plot will be produced to compare the LOCF analysis of change from baseline in trough
FEV1 at Day 28 to the weighted mean change from baseline on pulse rate (0-4 hours) at
Day 28 (Figure 8.3). This will take the adjusted differences from placebo and 95%
confidence intervals from Table 7.4 and the adjusted differences from placebo and 95%
confidence intervals from Table 8.37.
12.7.2.
ECG
A summary of ECG parameters will be produced. Each ECG parameter at every assessed
time point will be summarised using summary statistics (Table 8.38).
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A summary of the number and percentage of subjects who had abnormal and/or clinically
significant (as determined by the central cardiologist) ECG findings will be displayed by
treatment (Table 8.39).
A listing of ECG values and findings will also be produced (Listing 8.14 and Listing
8.15).
12.7.2.1.
QTc
Maximum change from baseline will be categorised and the categories summarised
(Table 8.42 and Table 8.43). Weighted mean change from baseline will be summarised
(Table 8.44 and Table 8.46). Weighted mean change from pre-dose will be summarised
(Table 8.45 and Table 8.47). The cumulative distribution of the maximum change from
baseline at 0-4 hours on each day will also be plotted (Figure 8.4 and Figure 8.5).
The change from baseline endpoints will also be analysed using ANCOVA as for derived
vital signs endpoints (see Section 12.7.1). Pairwise comparisons of each active treatment
versus placebo will be performed and treatment differences will be presented with 95%
confidence intervals (Table 8.48 to Table 8.53).
The following plots will also be produced:
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12.7.3.
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Summary statistics of fasting potassium and glucose will be presented and plotted for
each treatment group on Days 1 and 28 (Table 8.54, Figure 8.16, and Figure 8.17). The
changes from baseline relative to the normal range (shift tables) will also be produced for
fasting potassium and glucose (Table 8.55). Summary statistics of non-fasting potassium
only will be presented for each treatment group on Days 7 and 14 (Table 8.55). The
changes from baseline relative to the normal range (shift tables) will also be produced for
non-fasting potassium (Table 8.57).
Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on Days
7 and 14 will be used to derive the following endpoints (where baseline will be defined as
Visit 2 pre-dose):
Derived Endpoint
Maximum decrease from baseline (0-4 hours)
Weighted Mean Change from baseline (0-4 hours)
Maximum increase from baseline (0-4 hours)
Measure(s)
Fasting Potassium
Non-fasting Potassium
Fasting Potassium
Non-fasting Potassium
Glucose
Glucose
and will be analysed using ANCOVA with effects due to baseline value, centre grouping,
age, sex, baseline percent predicted FEV1 stratum and treatment group. Pairwise
comparisons of each treatment group versus placebo will be performed and treatment
differences will be presented with 95% confidence intervals (Table 8.70 to Table 8.72).
Summary statistics of change from baseline and change from pre-dose will also be
presented (Table 8.58 to Table 8.69).
All potassium and glucose data will be listed (Listing 8.16)
12.7.4.
Exacerbations
The number and percentage of subjects who had an asthma exacerbation, who took
corticosteroids for an exacerbation, who were hospitalised due to an exacerbation and
who had an emergency room (ER) visit due to an exacerbation, will be summarised
separately alongside the primary causes of asthma exacerbations (Table 8.76). All asthma
exacerbation data will be listed (Listing 8.17).
12.7.5.
Device Malfunction
Subjects with a Novel Dry Powder Inhaler malfunction will be listed with the primary
reason for malfunction (Listing 8.18).
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13.
13.1.
13.1.1.
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minutes, 10-30minutes). All NQ values will be set to missing in the PK dataset. Dataset
specifications are detailed in Attachment PK1.
13.1.2.
The sampling times will be relative to the time of the last dose of GW642444. Data from
subjects with inadequate dosing histories (no records for dosing time) or missing sample
information or data (sample not taken, insufficient sample for analysis) will be discarded
from the data file. Concentrations following an obvious missing dosing event will be
excluded from the PK analysis. All excluded observations or discarded data from the data
file along with reasons for exclusion will be listed in the report.
Some concentration results may be inconsistent with the expected PK behaviour of
GW642444. These data may be excluded from the modelling after investigation about
possible sampling/labelling errors. The exclusions will be listed.
13.1.3.
Covariates
Only subjects with a complete set of covariates and a GW642444 concentration will be
included for the first covariate analysis. If some covariates have no influence in this
analysis, then subjects with a missing value for these covariates may be added back into
the dataset in order to improve the final parameter estimates. These subjects, however,
must have values for all of the significant covariates in the model.
13.1.4.
Pharmacokinetic Analyses
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THETA () in NONMEM notation, are factors that are either measured or controlled.
Random effects include residual error (ERR), epsilon () in NONMEM notation, and
between subject random effects, ETA () in NONMEM notation.
The population PK mixed effects models include four basic components:
The structural PK model, which predicts the plasma concentration for a typical
patient as a function of time and dose.
The covariate model component, which describes the influence of fixed effects
(demography, disease, concomitant medications) on PK model population
parameters.
The residual error model components, which describes the underlying distribution of
the error in the measured PK variable.
A structural model is built first, including error models. Then significant and clinically
relevant covariates relationships are added, using a predefined strategy (stepwise
inclusion followed by stepwise deletion). The final model should contain no redundant
covariates but the strategy should ensure that no significant covariate was missed.
Initially the simplest structural model will be selected to use as a valid base model. This
assessment will be based on the following evaluations:
The simplest structural model to use as a valid base model will be based on smallest
objective function and by inspection of the pattern in the residual plots. The best
estimation method, the most appropriate between-subjects variance models, and the
residual error model, will be identified and the resulting model called a BASE model.
Selection of covariates by univariate analyses (reduction of objective function of at least
3.84) will then be made. In building the NONMEM model forwardly, the covariate with
highest correlation will be added to the base model to build the first intermediate
NONMEM model. It will be accepted if the decrease in the objective function () is >
3.841 for a single covariate (p-value<0.05). Likewise, the covariate with second highest
correlation will be added next to the existing intermediate NONMEM model if it meets
the same acceptance criteria. This forward building technique will continue until all the
potential influential covariates are in the model. All selected covariates will be added
together, the model fitted to data, and this will be assigned as the FULL model
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The covariates included in the best NONMEM model built by the forwarding technique
will be confirmed by removing one covariate at a time. Backward deletion will be
applied until no covariate can be removed without significantly increasing the objective
function, resulting in the FINAL model (likelihood ratio test at p<0.005, 1 df, objective
function drop of at least 7.88). If a confidence interval of structural parameters includes
the value zero, the effect is considered not significant and the model is further simplified
until all structural parameters are well estimated.
Acceptable population models should result in successful minimisation, with at least
three significant digits for any parameter, a successful estimation of the covariance, and
the absolute value of last iteration gradients greater than 10-3 but smaller than 100.
Confidence intervals of structural parameters should not include zero; absolute value of
correlation between two structural parameters should not be greater than 0.95.
Acceptable models should not lead to trends in the distribution of weighted residuals
versus model predictions and versus independent variable. They should not be oversensitive to initial estimates. The observations versus predictions data should be evenly
distributed around the unit line, as evidenced by series of diagnostic plots.
If constraints were applied on parameters, no final estimate should be equal to its
boundary.
13.2.
Pharmacokinetic-Pharmacodynamic Analysis
13.2.1.
13.2.2.
Pharmacokinetic-AE Analysis
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Dose-response Modelling
This will be a supporting analysis using the absolute trough FEV1 (mean of 23to 24h post
dose) and change from baseline FEV1. The objective of this population dose-response
modelling using non linear mixed effects is to derive a predictive population doseresponse relationship based on trough FEV1 (primary efficacy variable), if data allow.
The following parameters for GW642444 can be estimated including potency (ED50),
shape and maximum response (Emax) and associated inter- and intra-subject variability
in the model parameters. Any time dependency in drug effect (tachyphylaxis) as well as
patient factors (covariate) on pharmacodynamic effect can also be formally evaluated.
The modelling strategy will involve testing the population linear and non linear mixedeffect dose response analysis using the longitudinal trough FEV1 data using all treatment
groups including placebo. This type of model assumes a parametric form for dose versus
response (including linear or Emax model) and normally distributed random effects for
individuals and for treatment response within individuals. Various PD models including
step, step-linear or variant Emax models may be explored. The shape of the dose
response curve will be informally tested by expanding the model in a logical manner with
progressively more parameters. Once a full model is developed , the significance of its
parameters will be formally tested by independently removing each one from the full
model and performing a likelihood ratio test that compares the difference in goodness of
fit (-2 ln likelihood) between the reduced model and the full model to its reference, chisquare distribution. Confidence intervals on parameter estimates will be obtained from
either the usual approximate asymptotic covariance matrix of the estimates or by using
non parametric bootstrapping method.
13.2.4.
The time course of FEV1 profile (absolute and/or % change from baseline) on day 1, 14
and day 28 will be simultaneously characterised (if possible) using a K-PD model
paradigm which extracts information about kinetic parameters that contributes towards
pharmacodynamic response using the full pulmonary pharmacodynamic profiles over a
wide dose range (Gabrielsson et al , 2000 - Biopharm Drug Dispos 21, 41-52). This
longitudinal non linear mixed effect modelling would allow estimation of the parameters
describing turnover of response (time to a 200mL and 12% increase from baseline in
FEV1 (0-4hr), time dependency in FEVl change) and pharmacodynamic characteristics
(potency and intrinsic efficacy). Confidence intervals on all derived parameter estimates
will be obtained from either the usual approximate asymptotic covariance matrix of the
estimates or by using non parametric bootstrapping method.
14.
If PGx analyses are required, they will be detailed in a separate analysis plan.
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REFERENCES
GlaxoSmithKline Document Number GM2006/00690/03. Study B2C109575. A doubleblind placebo-controlled study to evaluate the efficacy (measured by clinic FEV1,
bronchodilator response to salbutamol/albuterol, daily PEF, symptoms, rescue
salbutamol/albuterol use and withdrawals due to lack of efficacy), safety (assessed by
adverse events, clinical laboratory evaluations, ECGs and vital signs) and
pharmacokinetics of five doses (3mcg, 6.25mcg, 12.5mcg, 25mcg and 50mcg) of
GW642444M administered once daily compared with placebo over a 28 day treatment
period in subjects with persistent asthma.
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16.
ATTACHMENTS
16.1.
Study Population
Tables
Table 6.1 Summary of Subject Populations
Table 6.2 Summary of Reasons For Withdrawal Prior to Randomisation
Table 6.3 Summary of End of Study Record
Table 6.4 Summary of Attendance at Each Clinic Visit
Table 6.5 Summary of Number of Subjects by Centre
Table 6.6 Summary of Inclusion/Exclusion Criteria Deviations
Table 6.7 Summary of Protocol Deviations
Table 6.8 Summary of Demographic Characteristics
Table 6.9 Summary of Demographic Characteristics Per Protocol Population
Table 6.10 Summary of Race and Racial Combinations
Table 6.11 Summary of Race and Racial Combination Details
Table 6.12 Summary of History of Tobacco Use at Visit 1 (Screening)
Table 6.13 Summary of Duration of Asthma and Asthma History
Table 6.14 Summary of Current Medical Conditions
Table 6.15 Summary of Asthma Concomitant Medications Taken Pre-Treatment
Table 6.16 Summary of Asthma Concomitant Medications Taken During Treatment
Table 6.17 Summary of Asthma Concomitant Medications Taken Post Treatment
Table 6.18 Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
Table 6.19 Summary of Non-Asthma Concomitant Medications Taken During Treatment
Table 6.20 Summary of Non-Asthma Concomitant Medications Taken Post Treatment
Table 6.21 Summary of Screening Lung Function Test Results
Table 6.22 Summary of Treatment Compliance (%)
Table 6.23 Summary of Percent Predicted FEV1 Strata: As Randomised and Actual
Table 6.24 Summary of Percent Predicted FEV1 (%) Day 1 Pre-Dose by Actual Stratum
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Figures
Figure 6.1 Subject Withdrawals Over Time
Figure 6.2 Subject Withdrawals due to Lack of Efficacy Over Time
Efficacy
Tables
Table 7.1 Summary of Trough FEV1 (L) (LOCF) Intent-to-Treat
Table 7.2 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF)
Intent-to-Treat
Table 7.3 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF)
Excluding Placebo - Intent-to-Treat
Table 7.4 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) Intent-to-Treat
Table 7.5 Summary of Trough FEV1 (L) (LOCF) Per Protocol
Table 7.6 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF) Per
Protocol
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Table 7.7 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) Per Protocol
Table 7.8 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (Repeated
Measures)
Table 7.9 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated
Measures)
Table 7.10 Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Table 7.11 Summary of Change from Baseline in Trough FEV1 (L) at Day 28 by Stratum
Table 7.12 Slope Estimate of Change from Baseline in Trough FEV1 (L) (LOCF) by
Stratum
Table 7.13 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) by
Stratum
Table 7.14 Summary of Raw Serial FEV1 (L)
Table 7.15 Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4 hours)
Table 7.16 Summary of Percentage Change from Baseline in Serial FEV1 (L) (0-4 hours)
Table 7.17 Summary of Weighted Mean Change from Baseline in 24 Hour Serial Clinic
FEV1 (L)
Table 7.18 Statistical Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). All Subjects, including 6-12 hour time points
Table 7.19 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). All Subjects excluding 6-12 hour time points
Table 7.20 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Subset of Subjects who had the 6-12 hour time points
measured. All time points included
Table 7.21 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Subset of Subjects who had 6-12 hour time points
measured, excluding 6-12 hour time points
Table 7.22 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Observations without rescue medication
Table 7.23 Summary of Post-salbutamol/albuterol FEV1 (L)
Table 7.24 Summary of Post-salbutamol/albuterol FEV1 (L) Differences
Table 7.25 Statistical Analysis of difference in post-salbutamol/albuterol FEV1
Table 7.26 Summary of Maximum Increase from Baseline in FEV1 (L) (0-4hr)
Table 7.27 Statistical Analysis of Maximum Increase from Baseline in FEV1 (L) (0-4
hours)
Table 7.28 Summary of Weighted Mean Change from Baseline in FEV1 (L) (0-4hr)
Table 7.29 Statistical Analysis of Weighted Mean Change from Baseline in FEV1 (L) (04 hours)
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Table 7.30 Summary of the Proportion of Subjects Obtaining 200mL and 12%
increase from Baseline FEV1 (L) (0-4hr)
Table 7.31 Summary of the Cumulative Proportion of Subjects Obtaining 200mL and
12% increase from Baseline FEV1 (L) (0-4hr)
Table 7.32 Summary of the Proportion of Subjects Obtaining 15% increase from
Baseline FEV1 (L) (0-4hr)
Table 7.33 Summary of the Cumulative Proportion of Subjects Obtaining 15% increase
from Baseline FEV1 (L) (0-4hr)
Table 7.34 Summary of Peak Post-Dose FEV1 (L) (0-4 hours)
Table 7.35 Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4 hours)
Table 7.36 Summary of Ratio of Peak Post-Dose FEV1 to Trough FEV1
Table 7.37 Change from Baseline in PM PEF (L/min)
Table 7.38 Statistical Analysis of Change from Baseline in PM PEF (L/min)
Table 7.39 Change from Baseline in AM PEF (L/min)
Table 7.40 Statistical Analysis of Change from Baseline in AM PEF (L/min)
Table 7.41 Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Table 7.42 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
24 Hour Periods
Table 7.43 Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Table 7.44 Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24
Hour Periods
Table 7.45 Change from Baseline in Percentage of Symptom Free Days
Table 7.46 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
Days
Table 7.47 Change from Baseline in Percentage of Symptom Free Nights
Table 7.48 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
Nights
Table 7.49 Change from Baseline in Percentage of Rescue Free Days
Table 7.50 Statistical Analysis of Change from Baseline in Percentage of Rescue Free
Days
Table 7.51 Change from Baseline in Percentage of Rescue Free Nights
Table 7.52 Statistical Analysis of Change from Baseline in Percentage of Rescue Free
Nights
Table 7.53 Statistical Analysis of Withdrawals Due to Lack of Efficacy
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Figures
Figure 7.1 Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 Intent-to-Treat
Figure 7.2 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Intent-to-Treat
Figure 7.3 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
Figure 7.4 Empirical Distribution Function for Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Intent-to-Treat
Figure 7.5 Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 Per Protocol
Figure 7.6 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Per Protocol
Figure 7.7 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol
Figure 7.8 Empirical Distribution Function for Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Per Protocol
Figure 7.9 Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)
Figure 7.10 Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)
Differences from Placebo
Figure 7.11 Adjusted Treatment Differences of Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28, by Stratum
Figure 7.12 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at
Day 28, by Stratum
Figure 7.13 Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
Figure 7.14 Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean
24 hour Serial FEV1 (L)
Figure 7.15 Plot of Mean Clinic FEV1 (L) Over Time
Figure 7.16 Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Figure 7.17 Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Figure 7.18 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 Day 1
Figure 7.19 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 1 Screening
Figure 7.20 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 Screening
Figure 7.21 Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4 hours)
Figure 7.22 Mean Change from Baseline in PM PEF (L/min)
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Safety
Tables
Table 8.1 Summary of Exposure
Table 8.2 Summary of On-Treatment Adverse Events
Table 8.3 Summary of Post-Treatment Adverse Events
Table 8.4 Summary of Most Frequent On-Treatment Adverse Events
Table 8.5 Summary of Drug-Related Adverse Events
Table 8.6 Summary of Adverse Events Leading to Permanent Discontinuation of Study
Drug or Withdrawal From the Study
Table 8.7 Summary of Pre-Treatment Serious Adverse Events
Table 8.8 Summary of On-Treatment Serious Adverse Events
Table 8.9 Summary of Post-Treatment Serious Adverse Events
Table 8.10 Relationship of Adverse Event System Organ Class, Preferred Term and
Verbatim Text
Table 8.11 Summary of Chemistry Data
Table 8.12 Summary of Chemistry Data Outside the Normal Range
Table 8.13 Summary of Chemistry Changes from Baseline Relative to the Normal Range
Table 8.14 Summary of Haematology Data
Table 8.15 Summary of Haematology Data Outside the Normal Range
Table 8.16 Summary of Haematology Changes from Baseline Relative to the Normal
Range
Table 8.17 Summary of Urine Dipstick Results
Table 8.18 Summary of Vital Signs
Table 8.19 Summary of Change from Baseline in Vital Signs
Table 8.20 Summary of Maximum Increase from Baseline in Systolic Blood Pressure (04 hrs)
Table 8.21 Summary of Maximum Increase from Pre-Dose in Systolic Blood Pressure (04 hrs)
Table 8.22 Statistical Analysis of Maximum Increase from Baseline in Systolic Blood
Pressure (0-4 hrs)
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Table 8.23 Summary of Maximum Decrease from Baseline in Diastolic Blood Pressure
(0-4 hrs)
Table 8.24 Summary of Maximum Decrease from Pre-Dose in Diastolic Blood Pressure
(0-4 hrs)
Table 8.25 Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood
Pressure (0-4 hrs)
Table 8.26 Summary of Maximum Increase from Baseline in Pulse Rate (0-4 hrs)
Table 8.27 Summary of Maximum Increase from Pre-Dose in Pulse Rate (0-4 hrs)
Table 8.28 Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (0-4
hrs)
Table 8.29 Summary of Weighted Mean Change from Baseline in Systolic Blood
Pressure (0-4 hours)
Table 8.30 Summary of Weighted Mean Change from Pre-Dose in Systolic Blood
Pressure (0-4 hours)
Table 8.31 Statistical Analysis of Weighted Mean Change from Baseline in Systolic
Blood Pressure (0-4 hours)
Table 8.32 Summary of Weighted Mean Change from Baseline in Diastolic Blood
Pressure (0-4 hours)
Table 8.33 Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood
Pressure (0-4 hours)
Table 8.34 Statistical Analysis of Weighted Mean Change from Baseline in Diastolic
Blood Pressure (0-4 hours)
Table 8.35 Summary of Weighted Mean Change from Baseline in Pulse Rate (0-4 hours)
Table 8.36 Summary of Weighted Mean Change from Pre-Dose in Pulse Rate (0-4
hours)
Table 8.37 Statistical Analysis of Weighted mean change from baseline in Pulse Rate (04 hours)
Table 8.38 Summary of ECG Values
Table 8.39 Summary of ECG Findings
Table 8.40 Summary of Maximum Post-Dose QTc (F) Interval (msec)
Table 8.41 Summary of Maximum Post-Dose QTc (B) Interval (msec)
Table 8.42 Summary of Maximum Change from Baseline (0-4 hours) in QTc (F) Interval
(msec)
Table 8.43 Summary of Maximum Change from Baseline (0-4 hours) in QTc (B) Interval
(msec)
Table 8.44 Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc (F)
Interval (msec)
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Table 8.45 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc (F)
Interval (msec)
Table 8.46 Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc (B)
Interval (msec)
Table 8.47 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc (B)
Interval (msec)
Table 8.48 Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F)
(msec)
Table 8.49 Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B)
(msec)
Table 8.50 Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs)
QTc (F) (msec)
Table 8.51 Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs)
QTc (B)
Table 8.52 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc
(F)
Table 8.53 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc
(B)
Table 8.54 Summary of Fasting Potassium and Glucose
Table 8.55 Summary of Non-fasting Potassium
Table 8.56 Summary of Fasting Potassium and Glucose Changes from Baseline Relative
to the Normal Range
Table 8.57 Summary of Non-fasting Potassium Changes from Baseline Relative to the
Normal Range
Table 8.58 Summary of Maximum Decrease from Baseline in Fasting Potassium (0-4
hrs)
Table 8.59 Summary of Maximum Decrease from Pre-Dose in Fasting Potassium (0-4
hrs)
Table 8.60 Summary of Maximum Decrease from Baseline in Non-Fasting Potassium (04 hrs)
Table 8.61 Summary of Maximum Decrease from Pre-Dose in Non-Fasting Potassium
(0-4 hrs)
Table 8.62 Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)
Table 8.63 Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)
Table 8.64 Summary of Weighted Mean Change from Baseline in Fasting Potassium (0-4
hrs)
Table 8.65 Summary of Weighted Mean Change from Pre-Dose in Fasting Potassium (04 hrs)
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Table 8.66 Summary of Weighted Mean Change from Baseline in Non- Fasting
Potassium (0-4 hrs)
Table 8.67 Summary of Weighted Mean Change from Pre-Dose in Non- Fasting
Potassium (0-4 hrs)
Table 8.68 Summary of Weighted Mean Change from Baseline in Glucose (0-4 hrs)
Table 8.69 Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4 hrs)
Table 8.70 Statistical Analysis of Maximum Decrease from Baseline in Fasting
Potassium (0-4 hrs)
Table 8.71 Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting
Potassium (0-4 hrs)
Table 8.72 Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)
Table 8.73 Statistical Analysis of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs)
Table 8.74 Statistical Analysis of Weighted Mean Change from Baseline in Non- Fasting
Potassium (0-4 hrs)
Table 8.75 Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4
hrs)
Table 8.76 Summary of Subjects with Asthma Exacerbations
Figures
Figure 8.1 Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline LFT
Values
Figure 8.2 Box Plot of Maximum Post-Baseline Liver Function Tests
Figure 8.3 Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted Mean
Pulse Rate at Day 28
Figure 8.4 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F)
Interval (msec)
Figure 8.5 Empirical Distribution Function for Maximum Change in QTc (B) Interval
Figure 8.6 Mean (95% CI) Change from Baseline in QTc (F) Interval by Time and
Treatment
Figure 8.7 Mean (95% CI) Change from Baseline in QTc (B) Interval by Time and
Treatment
Figure 8.8 Adjusted Treatment Differences (95% CI) of Change from Baseline in PostDose Serial QTc(F) (msec)
Figure 8.9 Adjusted Treatment Differences (95% CI) of Change from Baseline in PostDose Serial QTc(B) (msec)
Figure 8.10 Serial QTc(F) (msec) versus Heart Rate (beats/min)
Figure 8.11 Serial QTc(F) (msec) versus Heart Rate (beats/min)
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Pharmacokinetics
Tables
Table 9.1 Summary of % of NQ values by treatment, day & time for GW642444,
triphenyacetate, GW630200 & GSK932009
Table 9.2 Estimated Population PK Parameter means and their 95% Confidence
Intervals BASE PK model
Table 9.3 Summary of Covariate Analysis
Table 9.4 Estimated PK Parameter means and their 95% Confidence Intervals FINAL
PK Model
Table 9.5 Estimated Population PK Parameter means and their 95% Confidence Intervals
Systemic PK/PD model
Table 9.6 Estimated Population PK Parameter means and their 95% Confidence Intervals
DR model
Table 9.7 Estimated Population PK Parameter means and their 95% Confidence Intervals
K/PD model
Figures
Figure 9.1 Goodness of fit plots for base PK model
Figure 9.2 Plots of base model PK parameter estimates versus influential covariates, if
applicable
Figure 9.3 Goodness of fit plots for final PK model
Figure 9.4 Scatter Plot of PD endpoints versus GW62444 Cmax
Figure 9.5 Goodness of fit plots for PK/PD models
Figure 9.6 Goodness of fit plots for DR and K/PD models
Listings
Listing 9.1 Concentration time for GW642444
Listing 9.2 Concentration time for triphenylacetate
Listing 9.3 Concentration time for GW630200
Listing 9.4 Concentration time for GSK9322009
Listing 9.5 NONMEM PK data file for GW642444
Listing 9.6 NONMEM output files from the Base & Final Models PK
Listing 9.7 NONMEM control files from Base & Final Models PK
Listing 9.8 NONMMEM systemic PK/PD data file for GW642444
Listing 9.9 NONMEM output files from systemic PK/PD modelling
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16.2.
The data display shells are contained in separate documents which are available on
request.
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where:
FEV1 = FEV1 value
BL = baseline FEV1 value
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The file structure is a space-delimited file with each row containing the following
columns of information.
Order
in File
1
2
3
Variable
short name
STUD
POP
ID
Assessment
description
Study identifier
Study population
NONMEM
Identifier
Patient identifier in
study
Format
Unit
Integer
Interger
Interger
109575
0=Asthmatics
500 to n
SUBJ
Varchar
PERD
Study Visit
Varchar
DAY
Study day
Varchar
DRUG
Name of drug
Varchar
8
9
10
11
DEV
FORM
DGRP
AMT
Device
Formulation
Treatment
Dose given
Interger
Interger
Decimal
Decimal
Mcg
Mcg
12
TRLD
Decimal
13
TIME
Decimal
14
CONC
Decimal
pg/mL
15
MDV
Integer
16
EVID
Event identifier.
Integer
60
float (15.5)
Missing values are represented by .
At dosing times (when AMT is
positive), CONC should be .
Either 0 if drug concentration value
present or 1 if missing value or
EVID=1
Flag indicating whether LABL
contains dosing admin info or drug
concentration data.
Valid values are 1 each dosing record for subject
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in File
Variable
short name
Assessment
description
Format
Unit
17
LABL
Record label
Varchar
18
ROUT
Character
19
RATE
Route of
administration
Rate of infusion for
intravenous study
Decimal
g/h
20
AGE
Age
Decimal
yrs
21
WT
Weight
Decimal
kg
22
HT
Height
Decimal
cm
23
SEX
Subject gender
Enum
24
25
26
ETHN
RACE
BMI
Subject ethnicity
Subject race
Body mass index
Enum
Enum
Decimal
kg/m^2
27
28
SMOK
II
Smoking habits
Interdose interval
I Integer
decimal
29
ADDL
Additional dose
integer
30
31
AMPM
DATETIME
Interger
YYYY-MMDD
HH:MM:SS
32
STRATA
FEV1 stratum
Enum
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Variable
short name
Assessment
description
Format
CONMED
Interger
CENT
Enum
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NOTE only active doses to be included in the dataset as identified below for calculation
of TIME
* Calculation of TRLD
Visit 2 (Day 1), samples 2-5 - pm dose on Visit day (Day 1)
Visit 3 (Day 7), sample 1 pm dose on previous day to Visit (Day 6)
Visit 4 (Day 14), sample 1 pm dose on Visit day (Day 14)
Visit 5 (Day 28), sample 1 pm dose on previous day to Visit (Day 27)
Visit 5 (Day 28), samples 2-5 pm dose on Visit day (Day 28)
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P
I
D
SU
BJ
PE
RD
D
A
Y
DRU
G
D
E
V
FO
RM
DG
RP
A
M
T
TR
LD
TI
M
E
CO
NC
M
D
V
E
VI
D
LAB
L
RO
UT
RA
TE
A
G
E
W
T
H
T
S
E
X
ET
HN
B
M
I
II
AD
DL
AM
PM
DATE
TIME
CE
NT
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.
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The file structure is a space-delimited file with each row containing the following columns of information.
Order in
File
Format
Unit
STUD
SUBJ
Study identifier
Patient identifier in study
Integer
Varchar
2
3
4
5
6
7
8
PERD
DAY
DRUG
DEV
FORM
DGRP
AMT
LABL
Study Visit
Study day
Name of Drug
Device
Formulation
Treatment
Dose given
Record label
Varchar
Varchar
Varchar
Interger
Interger
Decimal
Decimal
Varchar
Mcg
Mcg
-
9
10
POP
AGE
Study Population
Age
Interger
Decimal
Yrs
11
12
13
WT
HT
SEX
Weight
Height
Patient gender
Decimal
Decimal
Enum
Kg
Cm
-
14
15
16
17
18
EtTHN
RACE
BHR
MR4
MR4C
Enum
Enum
XX.X
XX.X
XX.X
Bpm
Bpm
Bpm
19
20
WMR4
WR4C
Patient ethnicity
Patient race
Baseline heart rate
Maximum heart rate (0-4h)
Maximum change from baseline heart
rate (0-4h)
Weighted mean heart rate (0-4h)
Weighted mean change from baseline
109575
Maximum 10 characters (numeric or text). Different identifier for each
subject
Maximum 10 characters (numeric or text
Maximum 10 characters (numeric or text
Maximum 10 characters (numeric or text). GW642444
2=Novel dry powder inhaler
3=M-salt Magnesiun Sterearte
Dose group
AMT = 0 400
Maximum 32 characters (numeric or text),
Record identifier: LABL will be OBSERVATION
0=Asthmatics
Integer. Age in years at time of screening rounded down to give age
at last birthday.
Weight in kilograms at time of screening.
Height in centimetres at time of screening.
Integer. One of the following 1 = male
2 = female
Integer.
Integer.
Mean pre-dose HR
Max HR (0-4h)
Max change from baseline in HR (0-4h
XX.X
XX.X
Bpm
Bpm
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22
23
BP
MP4
MP4C
24
25
WP4
WP4C
26
27
BG
MG4
MG4C
28
29
WG4
WG4C
30
31
32
33
34
BQTB
MQTB4
MQTBC4
WQTB4
WQTBC4
35
36
37
38
39
BQTF
MQTF4
MQTFC4
WQTF4
WQTFC4
40
CENT
Format
Unit
XX.X
X.XX
XXX
Mmol/L
Mmol/L
Mmol/L
X.XX
X.XX
Mmol/L
Mmol/L
XX.X
X.XX
X.XX
Mmol/L
Mmol/L
Mmol/L
X.XX
X.XX
Mmol/L
Mmol/L
X.XX
X.XX
X.XX
X.XX
X.XX
msec
msec
msec
msec
msec
X.XX
X.XX
X.XX
X.XX
X.XX
msec
msec
msec
msec
msec
X.XX
X.XX
XX
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FEV1
FEV1C
Assessment description
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J
PER
D
DA
Y
DGR
P
AM
T
LABL
TLR
D
FEV
1
MD
V
EVI
D
CM
T
S
S
I
I
BAS
E
AG
E
WT
HT
SE
X
ETH
N
BMI
STRATU
M
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient
privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further
information please see the Patient Level Data section of the GSK Clincal Study Register.
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Argentina
Argentina
Argentina
ChairpersonArgentina
Chairperson-
Argentina
Chairperson-
1
Argentina
ChairpersonArgentina
CONFIDENTIAL
Argentina
Argentina
ChairpersonArgentina
Argentina
Chairperson-
YM2008/00019/00
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CONFIDENTIAL
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Investigator
Argentina
Argentina
ChairpersonArgentina
ChairpersonArgentina
Argentina
Chairperson-
CONFIDENTIAL
Chairperson-
Argentina
2
Chairperson-
Argentina
BELGIUM
Belgium
Belgium.
ChairpersonBelgium
Chairperson-
CANADA
Canada
Canada
ChairpersonCanada
Canada
YM2008/00019/00
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CONFIDENTIAL
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Canada
ChairpersonCanada
Canada
ChairpersonCanada
Chairperson-
Canada
Canada
Chairperson-
Canada
Canada
ChairpersonCanada
Chairperson-
CONFIDENTIAL
Canada
Canada
CHILE
Chile,
Chile
Chairperson-
Chile,
Chile,
Chairperson-
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Chairperson-
CONFIDENTIAL
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FRANCE
France
France
Chairperson- France
Chairperson-
France
France
ChairpersonDr. med.
Germany
Dr. med.
ChairpersonChairperson-
Germany
Germany
Germany
Dr.
med
Germany
Dr. Med.
MD
Germany
ChairpersonChairperson-
Germany
Dr. med.
Germany
Chairperson-
Germany
Dr. med.
Germany
Chairperson-
Germany
YM2008/00019/00
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CONFIDENTIAL
France
GERMANY
CONFIDENTIAL
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Investigator
Germany
Germany
Chairperson-
Dr. med.
Drs.
Germany
Chairperson-
Germany
KOREA
Korea
Korea
ChairpersonKorea
ChairpersonNETHERLAND
The
Netherlands
The Netherlands
The Netherlands
ChairpersonThe Netherlands
ChairpersonThe Netherlands
Chairperson-
The Netherlands
Peru
ChairpersonChairperson-
Peru
Peru
YM2008/00019/00
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Peru
CONFIDENTIAL
Korea
CONFIDENTIAL
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Peru
Peru
Chairperson-
PHILIPPINES
Philippines
Philippines
Chairperson
Chairperson
Philippines
Chairperson
Chairperson
POLAND
Poland
Poland
Chairperson-
Poland
Poland
Chairperson-
Poland
Poland
ChairpersonPoland
YM2008/00019/00
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Chairperson-
Poland
CONFIDENTIAL
Philippines
CONFIDENTIAL
B2C109575
Investigator
Poland
RUSSIAN FEDERATION
Russia
Chairperson-
Russian Federation
Russian Federation
Chairperson-
Chairperson-
Russia
Russian Federation
Chairperson-
Russia
Russia
ChairpersonRussia
ChairpersonRussian Federation
Chairperson-
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CONFIDENTIAL
Russian Federation
CONFIDENTIAL
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Investigator
Russian Federation
Russia
ChairpersonRussia
Russia
ChairpersonRussia
Chairperson-
Chairperson-
8
Russian
Federation
ChairpersonSOUTH AFRICA
CONFIDENTIAL
Russia
Russian Federation
South Africa
South
Africa
Chairperson-
South Africa
Chairperson-
South Africa
South Africa
Chairperson-
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South Africa
Chairperson-
South Africa,
South Africa
Chairperson-
SWEDEN
Sweden
Sweden
ChairpersonSweden
Sweden
THAILAND
9
Thailand
Chairperson-
Thailand
Chairperson-
CONFIDENTIAL
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Thailand
Thailand
UNITED STATES
Chairperson-
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MD
ChairpersonChairpersonMD
ChairpersonChairperson-
10
ChairpersonChairperson-
CONFIDENTIAL
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Chairperson-
ChairpersonChairperson-
10
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Chairperson-
ChairpersonChairpersonChairperson-
Co-ChairpersonCo-Chairperson-
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M.D.,
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Investigator
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This section contained Principal Investigators Curriculum Vitae and has been excluded to
protect Principal Investigator privacy.
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If the subject is unable to sign #1 below, then #2 must be completed (this can be done
by the parent/legal representative or medical staff).
(#1)
This study will look at genes in my blood. The study has been explained to me
and my questions answered. I would like to be in the study. The tube with my blood has
a number on it. If I decide later that I dont want to be in the study, my blood will be
thrown away. I can ask the study staff questions at any time.
Date: ________________ Signature: ________________________________
Day / Month / Year
(#2)
A copy of this Assent Form (signed and dated) must be given to the subjects
parent or legal representative.
Version No.: 01
Dated: 6 Nov 2007
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GSK will control access to its files that hold your coded information and results. Your
name will not appear in any publications or reports about this research.
GSK or those working with GSK (for example, other researchers) will only work with
your sample for the use stated in this consent. Samples will be stored securely. GSK
will require anyone who works with your sample to agree to hold the research
information and any individual results in confidence.
Medical information about you may be produced as part of the research or study
procedures. If at the time of the study, this information is known to be relevant to your
medical care it will be given to the study doctor who will be encouraged to share it with
you or your doctor. You will be told if any of this medical information requires
confirmation using a clinical test. This is important because some research results are
for research purposes and may have only limited relevance for clinical diagnosis or
treatment GSK will not release individual results to anyone else (e.g., family members,
primary care physicians, insurers, or employers) under any circumstance, unless
required by law.
GSK has taken appropriate measures to ensure the confidentiality of the researchrelated information. However, if you pass on your individual results (if obtained by you),
there is a possibility that this could have an affect on your insurance or employment.
This risk is similar as if you were to disclose any type of personal medical information to
a third party.
Medical information, samples and research results from you and other research
participants may be studied by GSK to make medicines or tests to determine the bodys
response to or handling of medicine. Your information and any results will be put in a
computer and stored in electronic databases. International regulations for information
on computers and relevant laws on processing personal information will be strictly
adhered to. Your information, sample, and results could be sent to other researchers
working with GSK and to other GSK sites.
By agreeing to take part in this research, you will allow your medical information,
sample, and pharmacogenetic results to be reviewed as part of collecting and analyzing
study results. The people who may check this research include GSK, people working
with GSK on this research, ethics committees and regulatory authorities (such as the
EMEA). These persons are required to maintain the confidentiality of the information.
WILL THERE BE COMPENSATION FOR PARTICIPATION IN THE RESEARCH?
You will not receive any payment for taking part in this pharmacogenetic research.
COMMERCIAL ISSUES
GSK and/or others intend to claim sole ownership of any research results consistent
with this consent. The results of this research may have commercial or intellectual
property value. By signing this consent, you agree that GSK can apply for patents and
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you understand that you will not receive any financial benefit that might come from the
research.
WHO CAN YOU CALL FOR MORE INFORMATION ABOUT THIS RESEARCH
STUDY?
You may contact __________ at telephone number __________ at any time if you have
questions about this study, an injury related to the blood draw for this research, or wish
to withdraw from this research. If you have questions about your rights as a research
subject, you may contact __________ of the Independent Ethics Committee at
telephone number________.
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CONSENT
A copy of this Consent Form (signed and dated) must be given to the subject
or legal representative.
GSK study code: B2C109575
My signature below indicates that:
1. I have read this form and the research has been explained to me.
2. I have been able to discuss the research and ask questions. I am satisfied with the
answers.
3. I have been given the time to consider whether or not to take part in this research.
4. I have freely decided to take part in the research study described in this form.
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Study Title
Study Identifier:
B2C109575
Sponsor:
GlaxoSmithKline (GSK)
Five Moore Drive
P.O. Box 13398
Research Triangle Park, NC 27709
Subject
Identification: __________________
Study Doctor: ___________________
Childs Initials________Date_________
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For some of the visits you will need to fast (nothing to eat or drink, except water) before
and during the visit. Your study doctor will explain this to you in more detail.
When you come to your doctors office, you will usually need to blow into a machine that
will tell the doctor how well you can breathe. On two of the visits you will need to do this
quite a few times throughout the day. You may occasionally feel lightheaded when
blowing into the machine. You will be asked questions about how you are feeling during
the study.
Your doctor will check your pulse and blood pressure and make tracings of your heart
rhythm throughout the morning on most of the visits. These are painless procedures.
At anytime during the study, tell your Mom or Dad [use country region descriptions] or
your guardian or the doctor if you feel sick.
Your doctor will give you a special device to take home with you to blow in every day that
will keep track of how well you are breathing. Your doctor will tell you how to use this
device. You will blow into the device in the morning and the evening before you take your
medication. You will also keep track of whether or not you used your medicine each day
and what your asthma symptoms are like each day. You will need to bring the device with
you to every visit. You need to tell your parents/guardian if your asthma gets worse or call
your doctor.
Your doctor or study staff will also give you a paper diary to keep track of how well you are
feeling. You will write down if you dont feel well and write down any medicines you take
when you dont feel well during the study. You will need to bring the card with you to every
visit.
When you come to your study doctors office you will have some blood taken for tests to
check your health. If you are a female this will include a pregnancy test at one of the
visits. The doctor will insert a small plastic tube into your vein to make taking blood
easier. This may be uncomfortable and will occasionally hurt, but only for a short time.
When you come into the doctors office at the start, and then again at the end of the study,
you will also be asked to give a small amount of urine (pee) [use country regional
description] in a cup for some tests to check your health. If you are a female this will
include a pregnancy test.
You do not have to be in the study if you don't want to. If you say yes now, you can still
say no at any time and stop later if you change your mind. No one will mind or be angry
with you if you say no. The doctor will still take care of you in exactly the same way. The
doctor will give you other medicine for your asthma.
Childs Initials________Date_________
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If you have any questions, you should ask your study doctor or his staff.
Sign your name below if you want to be in the study. Do not sign below if you do not want
to be in the study.
Childs Signature
Date
Parent/Guardians Signature
Date
Date
Childs Initials________Date_________
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Study Title
Study Identifier:
B2C109575
Sponsor:
GlaxoSmithKline (GSK)
Subject
Identification: __________________
Study Doctor:
Written Information Sheet
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Placebo is a powder that looks like the study drug but contains no medicine. Different
doses of the study drug are included to see which dose works best.
Some other drugs (taken by mouth or breathed in) are available for the treatment of
asthma. These include drugs which help to open the airways in the lungs (such as quick
relief medicines like albuterol/salbutamol [use country specific names]), and drugs which
help reduce inflammation (redness and swelling) in the airways of the lungs (inhaled
corticosteroids). If you decide not to be in this study, your study doctor will advise you
on which asthma drug or drugs you need to take and other things you need to do for
your asthma.
HOW MANY VISITS ARE REQUIRED?
You may be in this study up to 7 weeks and will need to visit with your study doctor
between 6 to 9 times.
The following visits will take place:
Approximate Time
required to spend
Visit No.
Time
at the Clinic
Screening
2-3hrs (between
Visit 1
Study Start
5PM and 10PM)
Screening
Rescreening (if required)
2-3hrs (between
Period
5PM and 10PM)
Randomisation
6 hours if not staying
overnight
27 hours if staying
Visit 2
2 Weeks after Visit 1
overnight
Visit 2a*
Treatment
9 hours
Visit 3
Treatment
1 Week after Visit 2
5 hours
Visit 4
Treatment
1 Week after Visit 3
5 hours
End of Treatment
6 hours if not staying
overnight
27 hours if staying
Visit 5
2 Week after Visit 4
overnight
Visit 5a*
Treatment
9 hours
Visit 6
Follow-up
1 Week after Visit 5
1 hour
* About half of all subjects will be required to remain at the clinic overnight at Visit 2 and
Visit 5. Your study doctor will discuss with you if this is a possible option or not. If you
do not stay overnight you will still need to return to the clinic the next day for Visits 2a
and 5a.
Visit Type
Visits 1 Screening Period: If you qualify for the study, you will keep taking your own
steroid inhaler and will be given a quick relief or rescue inhaler (albuterol/salbutamol
inhalation aerosol) to use for the relief of any asthma symptoms. Study procedures and
tests, described below, will be done to check your asthma. You will be asked to
describe any medical problems you have now and medical problems you have had in
the past (before this visit). You will also need to tell your doctor about any drugs you are
taking.
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At Visit 2: If you still qualify to be in the study you will be randomised to study drug.
Randomisation means that you are randomly (by chance, like flipping a coin) assigned to
one of the six study treatments. The group you are assigned to is chosen by a computer
program, without using any information about you. You will take your first dose of study
drug in the clinic at this visit.
You will receive one of the following six study drugs to be taken in the evening every day
for 4 weeks:
EVENING
3mcg GW642444M Inhaler
6.25mcg GW642444M Inhaler
12.5mcg GW642444M Inhaler
25mcg GW642444M Inhaler
50mcg GW642444M Inhaler
Placebo Inhaler
mcg = microgram
You will have a 1 out of 6 (17%) chance of receiving placebo.
Because this is a blinded study, neither you, your doctor, nor your study nurse, will
know what study drug (or placebo) you have been given. Your study doctor can find out
what drug you are on at any time if it is necessary to know this for your safety.
If you are not staying at the clinic overnight you will need to return to the clinic the
following day in the mid-morning for visit 2a.
Visits 3 and 4: During the 4 weeks of taking this drug, you will visit the clinic twice.
Study tests, listed below, will be done to check your asthma. The study doctor will
decide at each visit if you may continue to be in the study.
Visit 5/5a: This is the visit when you will stop taking the study drug. You will need to
return all study medication that has been provided to you for this study.
If you are not staying at the clinic overnight you will need to return to the clinic the
following day in the mid-morning for visit 5a.
Visit 6: This is the follow-up clinic visit and will happen 1 week after finishing the study
drug to see how you are feeling or if you have any questions about your asthma. You
will need to return all study related equipment and your rescue inhaler at this visit. Your
doctor will tell you what asthma drugs and other care you need for your asthma.
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You should refrain from using your quick reliever medication for 6 hours before
each visit (excluding follow-up Visit 6).
Please take your regular inhaled steroid as usual before you attend the clinic
visits.
You will need to fast (nothing to eat or drink except water) for at least 4 hours
before Visit 2 And Visit 5 until 4 hours after you take your dose of study drug at
the clinic.
Visit 2/2a and 5/5a:
Administration of study drug, and a check to see how well you are using your
inhaler.
Lung Function Tests (42 in total if you are staying in overnight, 36 in total if you are
not staying in overnight).
Blood Tests: Because blood will be taken a number of times during the visit a small
plastic tube (cannula) will be inserted into one of the veins in your arm. We will take
approximately 50mLs of blood (10 teaspoons full).
Urine sample to check health at Visit 5 only and pregnancy status (females only) at
Visit 2 and 5/5a.
Reversibility Test: You will be given a lung function test to measure your breathing
before and after you have been given a quick relief or rescue inhaler
(albuterol/salbutamol inhalation aerosol).
Once you have been randomised to receive study medication you should measure your
peak flow as follows:
Morning: before you take your steroid inhaler or any rescue medication
Evening: before your evening dose of study medication and before you take
your steroid inhaler or any rescue medication
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You will also be asked to write down on a specific piece of paper the times when you
feel sick, any drugs not related to this study that you may have started to take, or if you
have changed the amount of any drugs you are already taking.
Study Drug: You must take your study drug once every day in the evening (as your
doctor has told you), and bring all of the used and unused study drug with you to each
visit.
Visit 3 and 4:
Administration of study drug, and a check to see how well you are using your
inhaler.
Blood Tests: As we will take blood a number of times during the visit a small plastic
tube (cannula) may be inserted into one of the veins in your arm. We will take
approximately 30mLs of blood (6 teaspoons full).
Review of your electronic diary and return all study related equipment and
medication
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If this happens, you will be asked to complete the Early Withdrawal Visit, your study drug
will be collected, and your study doctor will recommend other drugs and care for your
asthma. If the study doctor is not your regular doctor, you will be asked to go back to
your regular doctor.
You should contact your study doctor if you decide to stop being in the study for any
reason. Your study doctor will tell you the best way for you to stop being in the study.
Although not expected, the company doing this study or the study doctor may decide
you should stop being in this study at any time for any of the following reasons:
It is not in the best interest of your health to continue the study medication
Something serious happens to you, which may need treatment
You do not follow your doctors instructions
The study is stopped or cancelled
You become pregnant.
Sometimes during the course of a research project, new information becomes available
about the drug that is being studied. If this happens, your doctor will tell you about the
new information and you can talk to your study doctor to decide if you want to stay in the
study. Any information and study data collected before you withdraw from the study will
be used at GSK, the company doing this study.
WHAT IF I AM TAKING AN INHALED CORTICOSTEROID AND LONG-ACTING beta2AGONIST COMBINATION TO CONTROL MY ASTHMA NOW?
If you are currently taking an inhaled corticosteroid (ICS) and long-acting beta2-agonist
(LABA) combination (e.g., Advair/Seretide, Symbicort) before you sign this consent form,
you may still be in this study if you and your doctor decide, but you will need to stop
taking your combination treatment 1 week before Visit 1. You will need to take an ICS
that has been prescribed to you throughout the study (Until Visit 6) but must stop taking
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the long-acting beta2-agonist (LABA) 1 week before Visit 1. You may take a quick relief
inhaler such as albuterol/salbutamol, in the 1 week before Visit 1, and during the study.
The study doctor will decide if your ICS and LABA combination can be changed to the
ICS by itself based on your current and past asthma history. If you stop or change any
medications to be in this study, there is a danger that your asthma may get worse.
Before changing any medication for this study, you will be told about all of the possible
risks and benefits of changing your medication and you must agree that you have been
told about these risks and benefits by signing this consent form. Changing your asthma
medication may cause your asthma symptoms to get worse. Risks include asthma that
gets worse, including immediate asthma attacks, more wheezing and breathing
problems than usual, using more quick relief medication (albuterol/salbutamol) than
usual, waking up more at night because of asthma, and having asthma symptoms on
more days than usual.
After talking about any possible changes in your medications with the study doctor and
the possible risks and benefits of these changes, it is your choice whether you want to
change your asthma medication to qualify to participate in this study. The study doctor
must agree your medicine can be switched based on your current and past asthma
history. If you decide you do not want to change asthma medications, then you will not
be able to take part in this study.
WHAT ARE THE EXPECTED RISKS FOR TAKING PART IN THE STUDY?
All drugs may cause side effects in some people. There are known side effects for the
study medications. Only you should take the study medication, and it must be kept out
of the reach of children and persons not able to read or understand.
WHAT ARE THE MOST COMMON SIDE EFFECTS FOR THE STUDY MEDICATION I
MAY RECEIVE DURING THIS TRIAL?
The drug being tested in this study may involve risks to you that are currently
unforeseeable. As with any new medicine that only a limited number of people have
taken, we dont yet know all its side effects. In any clinical trial, there is a risk of an unexpected, serious reaction to the study medicine, which could be life threatening.
Descriptions of all known possible side effects are listed below.
GW642444M
GW642444M is a long acting beta2 agonists. Long acting beta2 agonists have been
associated with the following side effects:
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Headaches
Muscle cramps (pain in the muscles)
Cardiac arrhythmias (abnormal heart rhythms when the heart beats too slow or too
fast or not on a regular rhythm) (rarely)
Inhaling any medicine can occasionally cause the airways to narrow for a short time,
leading to wheezing, shortness of breath and chest tightness. If that happens to you,
you will be given a quick relief inhaler to relieve your symptoms.
Data from a large clinical study in the United States has shown that subjects taking
salmeterol (insert trade name), which is also a long acting beta2 agonist, were at an
increased risk of serious respiratory-related events, including a small but significant
increase in deaths, from asthma problems when compared with those subjects taking
placebo. Further analyses suggest that this risk may be greater in African Americans.
Reproductive Risks
Pregnant or breast feeding women, or women planning to become pregnant cannot
participate in this study.
Aside from abstinence, even when you use one of the allowed contraceptive methods,
there may still be a small risk that you could become pregnant and your unborn baby
may have been exposed to one of the study drugs, which may involve unknown risks to
your baby, even if you stop taking the drug right away. So, if you think you are pregnant
or may become pregnant, you must tell your study doctor as soon as possible. If you do
become pregnant you will be required to withdraw from the study.
There are no studies with GW642444 in pregnant women. The safety of GW642444 in
pregnancy has been studied in several different types of animals. In the developing
offspring from these pregnant animals treated with GW642444, cleft palate, problems
with how bones form and join together, and eye lid changes were sometimes seen.
.
All females aged 12 years and older, except those who are pregnant, nursing or
planning to get pregnant during the time of the study, may be in this study.
If you choose to be in this study, you must use one of the allowed birth control methods
(a way to keep you from becoming pregnant) for the specified period of time before and
after you are in the study. Ask your doctor if you have any questions about these
choices and which might be best for you. The kinds of birth control methods allowed in
the study are:
Male partner who is sterile prior to the female subject entering into the study and is
the only sexual partner for that female subject
Implants of levonorgestrel (NORPLANT)
Injectable progestogen (DEPO-PROVERA)
Birth control pills (either combined estrogen/progestin or progestin only)
Any intrauterine device (IUD) with a documented failure rate of less than 1% per year
Females of childbearing potential who are not sexually active must commit to
complete abstinence from intercourse throughout the clinical trial, and for a period
after the trial to account for elimination of the drug (minimum of six days).
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All females will have a blood pregnancy test at Visit 1 and a urine pregnancy test Visit 2
and Visit 5/5a. The test at Visit 1 and Visit 2 must be negative for you to continue in the
study. Any female subject who becomes pregnant during the study will have to stop
being in the study right away.
Placebo
If you are randomised to receive placebo (which is a powder that looks like the study
drug but contains no medicine) the only active medicine you will receive as part of the
study is the quick relief or rescue inhaler. You will however need to keep taking your
own steroid inhaler. Your asthma may get worse, so your asthma symptoms, breathing
(lung function) and quick relief or rescue inhaler use will be checked closely to see if
your asthma is getting worse. Your study doctor will stop you from staying in the study if
your asthma is getting worse, before the condition of your asthma becomes unsafe. Let
your study doctor know if you feel your asthma is getting worse.
Study Rescue Medication (albuterol/salbutamol)
The quick relief or rescue inhaler (albuterol/salbutamol) is available by prescription.
Common side effects reported by people taking albuterol/salbutamol include:
Skin rashes, swelling in the face or mouth and throat, shortness of breath and/or
wheezing with or without a low blood pressure
Decrease of potassium (a chemical) in the blood stream
Tremor (shakiness of hands)
Headache
Hyperactivity
Tachycardia (fast heart beat)
Awareness of heart beating
Cardiac arrhythmias (abnormal heart rhythms when the heart beats too slow or too
fast or not on a regular rhythm)
Peripheral vasodilation (flushing of the skin)
Wheezing or trouble breathing after using an inhaler
Mouth and throat irritation
Muscle cramps (pain in the muscles)
WHAT OTHER POSSIBLE RISKS ARE THERE FOR BEING IN THIS STUDY?
During the breathing (lung function) tests, you may have shortness of breath, coughing,
feel light-headed or faint and/or have chest tightness. If any of these things should
happen to you, you will receive medical treatment.
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You will be asked to stop taking your quick reliever for a certain period of time prior to a
breathing test.
Although the study drug in this clinical trial is not known to cause liver problems, study
drug(s) can uncommonly cause liver injury, which is identified by blood tests, or the
appearance of or worsening of fatigue (feeling tired), nausea (feeling sick in your
stomach), vomiting, abdominal pain (pain in the stomach area), jaundice (yellow eyes
and/or skin), fever, or rash. Should you develop these signs, you must tell your doctor
right away. If your blood tests suggest a possible liver injury, you will be asked to return
to the clinic right away to assure your continued safety, and to do more testing to see if
your liver disease was caused by a virus, a gallbladder problem or some other liver
disease. This testing will include additional blood tests (approximately 1 teaspoon per
test), and may include a liver ultrasound (picture) or other liver tests. If this happens,
your study doctor will ask you to stop taking the study medication. Your safety will be
checked until your blood tests return to normal.
During the study at any time, but especially during the 4-week treatment phase of the
study, your asthma may get worse, stay the same, or get better. Even though the quick
relief inhaler may make you feel better, there is a chance that your asthma may get
worse. If you feel that your asthma is getting worse, use the quick relief inhaler given to
you. If your asthma does not get better after using this inhaler, call the study doctor at
the phone number listed on this form or go to the emergency room for medical attention
right away.
When blood is taken for lab tests, you may feel slight pain or discomfort from the needle
stick in your vein and occasionally you may get a bruise or feel faint. Rarely, infection or
bleeding may develop where the needle entered the skin or vein.
You may experience slight skin irritation from the ECG pads, but this is generally mild
and resolves within a few days.
It is very important that you are able to make it to the clinic for all study visits, so you
need to think about the time needed and whether you can do this before you agree to be
in the study.
ARE THERE ANY BENEFITS FROM BEING IN THE STUDY?
A possible benefit of this study is having your asthma get better but this benefit cannot
be guaranteed. Although this study may not be of direct benefit to you, you may receive
helpful information about asthma and its treatment from being in this study. Also,
discovery of new medicines may provide benefits to other people with asthma and new
ways to manage asthma.
WHAT PAYMENTS WILL BE MADE FOR THE STUDY?
There will be no cost to you for study medications or clinic visits. You will not be paid for
participating in the study; however, GSK has made provisions with the study doctor to
compensate you for the reasonable travel costs to and from study visits and for other
miscellaneous costs (such as expense for a meal).
You will be paid $
per visit, for a total of $
to compensate you for the travel
costs to and from study visits and for other miscellaneous costs if you complete this
study. If you have to stop being in the study before completing this study, or if the study
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ends early, you will receive a partial payment based upon the number of visits
completed.
WHO SHOULD YOU CONTACT TO ANSWER ANY QUESTIONS ON THE STUDY?
If you have any questions concerning this study, or if at any time you feel you have
experienced a research-related injury or a reaction to the study medication, you may
contact Dr.
at
or after hours at
.
If you have any questions about your rights as a study subject, you may call:
[Insert Independent Ethics Committee]
[and address]
[and phone number]
An independent ethics committee or institutional review board (IEC/IRB) is an
independent group of people who have reviewed this research study with the welfare of
the subject in mind.
IN THE EVENT YOU ARE INJURED IN THE STUDY, WHAT COMPENSATION WILL
BE AVAILABLE?
US required language:
If you are injured by the investigational medicine being studied or by any procedure that
is done to you as specified by the study, GSK will pay for reasonable and necessary
medical expenses to treat the injury that are not covered by your medical insurance.
GSK is not offering to compensate you for any other expenses; you do not give up any
of your legal rights by signing this form.
Required language for UK and other countries with local requirements:
If you are injured by a medicine or clinical procedure that you would not have been given
outside this study, you will be compensated. Your study doctor can give you a copy of
the compensation guidelines for this kind of injury.
WHO WILL HAVE ACCESS TO MEDICAL AND PERSONAL INFORMATION ABOUT
YOU THAT IS COLLECTED IN THIS STUDY?
If you decide to participate in the study, the study doctor and staff will collect medical
and personal information about you as part of doing the study. People who work for or
with GlaxoSmithKline, and others like the independent ethics committee or the
institutional review board (IEC/IRB) for the study or regulatory authorities responsible for
approving medicines, will have access to this information at the site in order to check
that the study is done properly. GlaxoSmithKline staff who see this information at the
site will keep it confidential.
The study site will also transfer to GSK some of the information it collects, in a coded
form. The information transferred will not include your name, initials, address, or other
Informed Consent Form
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direct identifiers. It will be assigned a code number that only the site can connect back
to your name.
Your permission to the study doctor and staff to use this information and share it with
GlaxoSmithKline and others as described below for the study doesnt automatically end
at a particular time.
You may decide not to sign this authorization (by signing this consent form), or you may
revoke this authorization in writing at any time. However, you can only participate in the
study if you authorize the use and disclosure of the information as described above. If
you decide not to sign this authorization/consent form, you will not be enrolled in the
study. If you sign this authorization and decide later to revoke this authorization, you will
be dropped from the study at that time. Information collected up to the time you revoke
this authorization will continue to be used as study data if it is scientifically appropriate to
do so.
While you are in the study, the study site will not share certain new medical information
about you that is created as part of the study (such as whether or not you are getting
study drug, or the results of certain tests) unless the study doctor decides it is medically
important to do so. This is done to stop the study results from being distorted. Once the
study is over, you will be given access to medical information about you that you are
entitled to see. At any time, you may ask your study doctor to let you see your personal
information, e.g., name and address and to correct it if necessary.
WHAT WILL GLAXOSMITHKLINE (GSK) DO WITH THE INFORMATION IT GETS?
GSK may use the information that the study doctor gives it (i.e. the coded information):
By storing and analyzing it electronically to find out what this study is telling us.
By sharing it with regulatory authorities that approve new medicines, or with groups
that check that research is done properly
By publishing the results of the study (this will not include any information that
directly identifies you)
By sharing it as part of research with other companies or universities for the purpose
of further understanding or developing this drug and with other GSK offices in this
country and in other countries. If the information is sent to another country, GSK will
apply the same level of protection to your information, to the extent permitted by
local law
By using it to plan new studies or other types of research or other medical purposes
related to the development of the drug.
WHAT WILL HAPPEN TO TISSUE SAMPLES (BLOOD and URINE) FROM THIS
STUDY?
Blood samples will be taken during the study to confirm subject eligibility and to assess
the effects of GW642444M. Blood samples collected will be coded to protect your
confidentiality and will be transferred to GSK or other researchers working with GSK.
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Samples will not be stored for longer than 15 years from the date the last subject has
completed the study.
HOW IS GLAXOSMITHKLINE INVOLVED?
This study is sponsored by GlaxoSmithKline (GSK). The study doctors and/or the
institutions are paid by GSK to conduct this research study.
SUBECTSs STATEMENT OF CONSENT
I have read the statements in this informed consent form for this study. The study
information and procedures have been explained to me by [insert name(s)] on [insert
date] during the consent process for this study.
I have had the opportunity to ask questions about this study, and answers and
explanations have been provided.
I have been given time and opportunity to read the information carefully, to discuss it
with others and to decide whether or not to take part in this study.
I authorize the use and disclosure of my personal information as described in this
document.
I agree to take part in this study.
Subjects Signature
Date
Signature of Legally
Acceptable Representative (LAR)
Date
Signature of Witness
Date
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Listing - ICH 6.2 Listing of Subjects with Inclusion / Exclusion Criteria Deviations
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Listing - ICH 6.3 Listing of Subjects for Whom the Treatment Blind was Broken
during the Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
13
41
Listing - ICH 7.1 Listing of Clinic Lung Function Data (Intent-to-Treat Population) . .
69
794
Listing - ICH 8.2 Listing of Subject Numbers for Individual Adverse Events
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
855
889
892
970
979
984
985
Listing - ICH 8.9 Listing of Adverse Events for Subjects not in Intent-to-Treat
Population (Not in Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .
986
Listing - ICH 8.10 Listing of Chemistry Data for Subjects With at Least One Normal
Range Abnormality (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
987
Listing - ICH 8.11 Listing of Haematology Data for Subjects With at Least One
Normal Range Abnormality (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
2848
Listing - ICH 8.12 Listing of Urinalysis Data for Subjects with Positive Dipstick
Results (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4148
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Listing - ICH 8.20 Listing of Exposure and Compliance Data Subjects Who
Received Treatment but Were Not Randomised (Total Population) . . . . . . . . . .
4282
Listing - ICH 8.21 Listing of Chemistry Data for Subjects With at Least One Normal
Range Abnormality Subjects Who Received Treatment but Were Not
Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4283
Listing - ICH 8.22 Listing of Haematology Data for Subjects With at Least One
Normal Range Abnormality Subjects Who Received Treatment but Were Not
Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4287
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
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25
30
31
59
88
141
Listing - Other 6.13 Listing of Relationship Between ATC Level 1, Ingredient and
Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1076
Listing - Other 6.101 Listing of Subjects with Compliance Greater than 110
Percent (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1129
1130
1738
2667
4738
5338
5340
5359
Listing - Other 8.23 Listing of Vital Signs Subjects Who Received Treatment but
Were Not Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5360
5361
5600
5837
6076
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Listing - Other 9.5 Observed GW642444 Cmax and tmax (estimated over period
2-30 mins post-dose) by Subject, Treatment and Visit . . . . . . . . . . . . . . . . . . . .
6315
6338
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
CONFIDENTIAL
Table 1
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the efficacy and
safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult subjects with
persistent asthma.
Data Management
Group
Randomisation
Company and
Address
Address
GlaxoSmithKline
BDS (Biomedical
Registration and
Data Sciences)
Medication
GlaxoSmithKline
Ordering System
R&D Ltd
(RAMOS)
Stockley Park West New Frontiers
Uxbridge
Science Park
Middlesex
Third Avenue
UB11 1BU
Harlow
Essex
CM19 5AW
Site of
Medical Writing:
Manufacture & Clinical Report
Assembly
Authorship
Names of authors
Address
and their Address
GlaxoSmithKlin
e GMS Ware
GlaxoSmithKline
Priority Street
R&D Ltd
Ware
Stockley Park
Hertfordshire
West
SG12 0DJ
Uxbridge
Middlesex
UB11 1BU
Site of
EU
release
Location of
Study Master
File
Address
GlaxoSmi
thKline
New
Frontiers
Science
Park,
Third
Avenue,
Harlow,
Essex,
CM19
5AW
Address
GlaxoSmithKline
New Frontiers
Science Park,
Third Avenue,
Harlow, Essex,
CM19 5AW
GCP
Regulatory
inspection
Name of
Agency
ANMAT
(Argentinian
Regulatory
Authority)
CONFIDENTIAL
Statistics Group
Medical Writing:
Study
Protocol
Sponsor
Authorship
Names of authors
Address
and their Address Address
GlaxoSmithKlin
S&P
e R&D Ltd
GlaxoSmithKline (Stats &
Stockley Park R&D Ltd
Programming)
West
Stockley Park
GlaxoSmithKline
Uxbridge
West
R&D Ltd
Middlesex
Uxbridge
Stockley Park West
UB11 1BU
Middlesex
Uxbridge
UB11 1BU
Middlesex
UB11 1BU
YM2008/00019/00
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Table 2
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Address of resource
(CSS)
GlaxoSmithKline
Argentina S.A.
Carlos Casares 3690
(1644) Victoria
Buenos Aires B1644 BCD
Centre Numbers
Address
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
Were Audits
done?
Centre Number
of Site(s)
yes/no
No
Centre numbers
Conducted by:
Name and
address of audit
group
YM2008/00019/00
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Laboratory name
and address
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Audits
CONFIDENTIAL
Country Name
Argentina
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
YM2008/00019/00
B2C109575
Conducted by:
CONFIDENTIAL
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Laboratorio de
Analisis
lnfectologicos y
ClinicosMonteagudo 218(4000) San Miguel
de TucumanArgentina
Laboratorio del
Hospital
Aeronautico
Central, Ventura de
la Vega 3697 Piso
3" (C1437HPA),
Ciudad Autonoma
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
GlaxoSmithKline
Rue du Tilleul 13
1332 GENVAL, Belgium
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
4
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Belgium
Conducted by:
CONFIDENTIAL
de Buenos Aires.
Argentina
Laboratorio
INSARES,
Rondeau 335,
(5500) Mendoza,
Argentina
Laboratorio del
Instituto Central de
Medicina, Calle 43
N585 (1900) La
Plata Buenos
Aires, Argentina
Laboratorio
Diagnostico Medico
S.R.L., Junin 1023
(C1113AAE)
Ciudad Autonoma
de Buenos Aires,
Argentina
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
YM2008/00019/00
B2C109575
Conducted by:
CONFIDENTIAL
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Canada
Dr
No
YM2008/00019/00
B2C109575
GlaxoSmithKline,
5 Moore Drive,
PO Box 13398,
Research Triangle
Park, NC 27709.
Conducted by:
CONFIDENTIAL
GlaxoSmithKline Canada
7333 Mississauga Road
Mississauga, Ontario
Canada
L5N 6L4
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Chile
GlaxoSmithKline
Av. Andres Bello 2687
Piso 21, Las Condes
Santiago, 7550611
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Conducted by:
CONFIDENTIAL
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
France
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
GlaxoSmithKline, 100
Route De Versailles,
78163 Marly Le Roi,
Cedex, France
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Conducted by:
CONFIDENTIAL
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
9
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Germany
Conducted by:
CONFIDENTIAL
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
YM2008/00019/00
B2C109575
10
Conducted by:
CONFIDENTIAL
10
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Centre Number
of Site(s)
Conducted by:
11
11
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
CONFIDENTIAL
GlaxoSmithKline BV,
Huis ter Heideweg 62
3705 LZ Zeist,
Netherlands
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
12
Peru
GlaxoSmithKline Peru,
Ave. Javier Prado Oeste
995
San Isidro,
Lima 27
Peru
12
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
Conducted by:
CONFIDENTIAL
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Philippines
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
13
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Conducted by:
CONFIDENTIAL
13
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Centre Number
of Site(s)
Conducted by:
GlaxoSmithKline
Commercial Sp
53 Rzymowskiego Street
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
14
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Yes
GSK - Worldwide
Regulatory
Compliance - UK
YM2008/00019/00
B2C109575
Poland
CONFIDENTIAL
14
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
YM2008/00019/00
B2C109575
15
Conducted by:
CONFIDENTIAL
15
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Centre Number
of Site(s)
Conducted by:
16
16
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
CONFIDENTIAL
GlaxoSmithKline Russia
Krylatskaya street 17,
build 3
121614 Moscow, Russia
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
South Africa
GlaxoSmithKline
SouthAfrica
Carisbrook Building,
The Campus,
57 Sloane Street
Bryanston 2021
Guateng, SouthAfrica
17
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Conducted by:
CONFIDENTIAL
17
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
South Korea
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
18
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
GlaxoSmithKline Korea
Ltd
9th Floor Kukje Centre
Bldg
191 Hangang-ro 2-ga,
Yongsangu
Seoul 140-702, Korea
Conducted by:
CONFIDENTIAL
18
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
GlaxoSmithKline AB
Box 516, Rasundavagen
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
19
GlaxoSmithKline
New Frontiers
Science Park, Third
No
YM2008/00019/00
B2C109575
Sweden
Conducted by:
CONFIDENTIAL
19
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
12
169 29 SOLNA, Sweden
YM2008/00019/00
B2C109575
20
Conducted by:
Avenue, Harlow,
Essex, CM19 5AW
CONFIDENTIAL
20
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Centre Number
of Site(s)
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Centre Number
of Site(s)
Conducted by:
21
GlaxoSmithKline Thailand
Ltd
12th Floor,
Wave Place,
55 Wireless Road,
Lumpini,
Patumwan, Bangkok
10330
21
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW
No
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
CONFIDENTIAL
Thailand
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Centre Number
of Site(s)
Conducted by:
United States
Dr
GlaxoSmithKline,
5 Moore Drive,
PO Box 13398, Research
Triangle Park, NC 27709.
22
GlaxoSmithKline,
5 Moore Drive,
PO Box 13398,
Research Triangle
Park, NC 27709.
Yes
GSK - Worldwide
Regulatory
Compliance
USA
GSK - Worldwide
Regulatory
Compliance Canada
YM2008/00019/00
B2C109575
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
CONFIDENTIAL
22
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
CONFIDENTIAL
Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.
Participating
Countries
Responsible for
which sites
Monitoring
Sites of
distribution in
Europe
Laboratory
Assessments
Audits
Were Audits
done?
Conducted by:
CONFIDENTIAL
23
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Centre Number
of Site(s)
YM2008/00019/00
B2C109575
23
CONFIDENTIAL
B2C109575
Statistical Appendix
TABLE OF CONTENTS
PAGE
3.
-1-
CONFIDENTIAL
2.
YM2008/00019/00
B2C109575
1.
CONFIDENTIAL
B2C109575
1.
SAS OUTPUT
1.1.
Primary Linear Trend Test Table 7.2: Linear Trend Test of Change from Baseline in Trough FEV1
(mL/mcg) (LOCF) Intent-to-Treat
YM2008/00019/00
B2C109575
-2-
CONFIDENTIAL
LinearTrendTestActualAnalysis14:25Friday,November7,20081
TheMixedProcedure
This section contained data from each individual patient, rather than in
Anonymized
data from each patient may be made available subject to
CONFIDENTIAL
B2C109575
1.2.
Primary Pairwise Comparisons Table 7.4: Statistical Analysis of Change from Baseline in Trough
FEV1 (L) (LOCF) Intent-to-Treat
YM2008/00019/00
B2C109575
- 13 -
CONFIDENTIAL
13
ChangefromBaselineActualAnalysis14:25Friday,November7,20081
TheMixedProcedure
This section contained data from each individual patient, rather than in
data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the
CONFIDENTIAL
B2C109575
1.3.
Supporting Pairwise Comparisons Table 7.7: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (LOCF) Per Protocol
YM2008/00019/00
B2C109575
- 27 -
CONFIDENTIAL
27
ChangefromBaselineActualAnalysis14:26Friday,November7,20081
TheMixedProcedure
This section contained data from each individual patient, rather than in
aggregate.
They have been excluded to protect patient privacy. Anonymized data
proposal. For further information please see the Patient Level Data section of the
CONFIDENTIAL
B2C109575
1.4.
Supporting Pairwise Comparisons Table 7.9: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (Repeated Measures)
YM2008/00019/00
B2C109575
- 42 -
CONFIDENTIAL
42
ChangefromBaselineActualAnalysis14:24Friday,November7,20081
TheMixedProcedure
information please see the Patient Level Data section of the GSK
CONFIDENTIAL
B2C109575
1.5.
Secondary Efficacy Comparisons Table 7.13: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (LOCF) at Day 28 by % Predicted FEV1 Stratum
YM2008/00019/00
B2C109575
- 122 -
CONFIDENTIAL
122
ChangefromBaselineActualAnalysis14:26Friday,November7,20081
TheMixedProcedure
This section contained data from each individual patient, rather than in
aggregate.
They have been excluded to protect patient privacy. Anonymized
research proposal. For further information please see the Patient Level Data
CONFIDENTIAL
B2C109575
1.6.
Secondary Efficacy Comparisons Table 7.20: Statistical Analysis of Weighted Mean Change
from Baseline in 24 Hour Serial Clinic FEV1 (L) All Subjects, including 6-12 hour time points
YM2008/00019/00
B2C109575
- 139 -
CONFIDENTIAL
139
Day1ofTreatmentPeriod14:25Friday,November7,20081
ActualModelChangeFromBaseline
TheMixedProcedure
This section contained data from each individual patient, rather than in
CONFIDENTIAL
B2C109575
1.7.
Safety Comparisons Table 8.37: Statistical Analysis of Weighted Mean Change from Baseline in
Pulse Rate (beats/min) (0-4 hrs)
YM2008/00019/00
B2C109575
- 217 -
CONFIDENTIAL
217
Day1ofTreatmentPeriod14:33Friday,November7,20081
ActualModelChangeFromBaseline
TheMixedProcedure
This section contained data from each individual patient, rather than in
research proposal. For further information please see the Patient Level Data
CONFIDENTIAL
B2C109575
1.8.
Safety Comparisons Table 8.70: Statistical Analysis of Maximum Decrease from Baseline in
Fasting Potassium (0-4 hrs)
YM2008/00019/00
B2C109575
- 377 -
CONFIDENTIAL
377
Day1ofTreatmentPeriod14:32Friday,November7,20081
StatisticalAnalysisofChangeFromBaselineinmaxdecrK_PLC(04hrs)
TheMixedProcedure
This section contained data from each individual patient, rather than in
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1.9.
Safety Comparisons Table 8.72: Statistical Analysis of Maximum Increase from Baseline in
Glucose (0-4 hrs)
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StatisticalAnalysisofChangeFromBaselineinmaxincrGLUCP_PLC(04hrs)
TheMixedProcedure
This section contained data from each individual patient, rather than in
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2.
2.1.
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16:00Friday,October31,2008
TheFREQProcedure
Tableofage2grpbyTRTCD
age2grpTRTCD(Randomizedtreatmentcode)
Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
1235|34|23|33|33|30|32|185
|35.79|23.47|33.33|34.02|30.30|32.00|
+++++++
3680|61|75|66|64|69|68|403
|64.21|76.53|66.67|65.98|69.70|68.00|
+++++++
Total9598999799100588
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LSMeanChangeestimates,addingintreatment*ageinteraction16:00Friday,October31,2008
_TRTCDage2grpEstimateStdErrProbtupplow
3mcg12350.12610.095300.18650.313230.06113
36800.065090.060700.28400.184310.05413
6.25mcg12350.030440.085540.72210.137570.19845
36800.11790.062010.05770.239720.00388
12.5mcg12350.0097930.085680.90900.178080.15850
36800.18780.062980.00300.311460.06405
25mcg12350.011050.087260.89930.160350.18245
36800.19220.061550.00190.313090.07128
50mcg12350.036600.086190.67120.205890.13268
36800.20610.062500.00100.328880.08337
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LSMeanChangeestimates,addingintreatment*ageinteraction,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008
_TRTCDage2grpEstimateStdErrProbtupplow
3mcg12350.16990.090410.06080.347470.00770
36800.067750.056320.22950.178380.04288
6.25mcg12350.047330.081870.56340.208150.11348
36800.11890.057540.03920.231960.00591
12.5mcg12350.048880.081240.54760.208460.11069
36800.19030.058440.00120.305100.07550
25mcg12350.070810.082120.38890.232120.09049
36800.20660.057270.00030.319060.09407
50mcg12350.11090.081110.17190.270250.04838
36800.21230.058020.00030.326250.09833
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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)4
LSMeanChangeestimates,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008
TRTCDEstimateStdErrProbtLowerUpper
3mcg0.081490.047510.08690.011830.1748
6.25mcg0.095730.047120.04270.0031790.1883
12.5mcg0.14610.047400.00220.052970.2392
25mcg0.16000.046840.00070.067990.2520
50mcg0.18930.04707<.00010.096890.2818
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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)5
checkageasacontinuousinteraction,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008
NumDen
EffectDFDFFValueProbF
TRTCD55551.580.1629
SEX15558.820.0031
AMALG115553.390.0001
AGE155527.47<.0001
FEVBL15554.890.0274
ASTRATUM15550.970.3242
AGE*TRTCD55552.440.0335
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LSMeanChangeestimates,addingintreatment*sexinteraction16:00Friday,October31,2008
_TRTCDSEXEstimateStdErrProbtupplow
3mcgF0.070830.067660.29560.203720.06207
M0.062380.077700.42240.215000.09023
6.25mcgF0.0020090.067860.97640.135290.13128
M0.14570.076410.05710.295770.00442
12.5mcgF0.11250.066460.09090.243080.01799
M0.15550.078800.04900.310250.00068
25mcgF0.11130.064630.08570.238190.01568
M0.13530.081310.09680.294990.02445
50mcgF0.15260.066630.02240.283500.02174
M0.17640.078300.02470.330160.02257
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FEVBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVBLBaselineFEV1
Std
CentreIDNMeanDevMinMax
33.220.922.324.16
11.98.1.981.98
22.790.352.543.04
11.72.1.721.72
11.79.1.791.79
12.22.2.222.22
22.570.142.472.68
22.110.112.032.19
23.150.282.953.35
31.700.501.302.27
11.75.1.751.75
12.97.2.972.97
11.53.1.531.53
11.24.1.241.24
22.800.212.652.95
12.42.2.422.42
11.63.1.631.63
12.06.2.062.06
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42.220.561.402.62
12.77.2.772.77
11.98.1.981.98
21.460.041.431.49
21.620.321.401.85
21.630.281.431.83
12.68.2.682.68
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FEVBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVBLBaselineFEV1
Std
CentreIDNMeanDevMinMax
22.880.012.872.88
12.91.2.912.91
11.65.1.651.65
12.82.2.822.82
12.39.2.392.39
12.55.2.552.55
22.041.141.232.85
12.40.2.402.40
12.56.2.562.56
22.070.082.022.13
32.120.231.912.37
21.990.131.902.08
12.35.2.352.35
12.24.2.242.24
32.610.941.933.68
21.850.241.682.01
11.79.1.791.79
11.43.1.431.43
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11.95.1.951.95
31.480.191.271.61
21.370.590.951.79
102.790.841.664.47
11.79.1.791.79
61.700.420.932.11
31.630.321.271.82
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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)9
FEVBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVBLBaselineFEV1
Std
CentreIDNMeanDevMinMax
21.650.751.122.18
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TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)
CentreIDNMeanStdDevMinimumMaximum
30.210.490.770.17
10.17.0.170.17
20.140.140.040.23
10.11.0.110.11
10.20.0.200.20
10.08.0.080.08
20.040.000.040.04
20.100.860.520.71
20.520.130.430.61
30.150.030.180.12
10.00.0.000.00
10.11.0.110.11
10.22.0.220.22
10.07.0.070.07
20.000.010.010.01
10.36.0.360.36
10.25.0.250.25
10.05.0.050.05
40.210.230.030.51
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10.45.0.450.45
10.06.0.060.06
20.190.220.030.35
20.380.020.360.39
20.120.300.100.33
10.14.0.140.14
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TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)
CentreIDNMeanStdDevMinimumMaximum
20.110.280.090.31
10.24.0.240.24
10.38.0.380.38
10.53.0.530.53
10.94.0.940.94
10.70.0.700.70
20.010.140.110.09
10.13.0.130.13
10.28.0.280.28
20.440.200.300.58
30.010.290.260.33
20.200.150.090.31
10.93.0.930.93
10.22.0.220.22
30.120.170.020.31
20.891.280.021.79
10.16.0.160.16
10.07.0.070.07
10.24.0.240.24
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30.470.190.320.68
20.560.130.470.65
100.530.580.061.73
10.07.0.070.07
60.000.060.050.10
30.190.460.150.71
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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)12
TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008
TheMEANSProcedure
AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)
CentreIDNMeanStdDevMinimumMaximum
20.030.130.070.12
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AnyBronchodilatorUseDuringAnyClinicVisit16:00Friday,October31,2008
TheFREQProcedure
TableofAnyBronchbyTRTCD
AnyBronchTRTCD(Randomizedtreatmentcode)
Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
N|60|78|83|81|86|90|478
|63.16|79.59|83.84|83.51|86.87|90.00|
+++++++
Y|35|20|16|16|13|10|110
|36.84|20.41|16.16|16.49|13.13|10.00|
+++++++
Total9598999799100588
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AnyBronchodilatorUseDuringLastClinicVisit(Day7orlater)16:00Friday,October31,2008
TheFREQProcedure
TableofBronchAtLastVisbyTRTCD
BronchAtLastVis
TRTCD(Randomizedtreatmentcode)
Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
N|71|87|93|93|97|93|534
|74.74|88.78|93.94|95.88|97.98|93.00|
+++++++
Y|24|11|6|4|2|7|54
|25.26|11.22|6.06|4.12|2.02|7.00|
+++++++
Total9598999799100588
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3.
BAYESIAN ANALYSES
3.1.
Tables
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Population:IntenttoTreat
Table30.1
BayesianAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)onDay28
3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)
BayesianAnalysisAssuming
NoninformativePrior
n98999799100
PosteriorMeanDifference(SD)0.0630.0690.1300.1210.161
(0.0509)(0.0505)(0.0508)(0.0500)(0.0502)
95%CredibleInterval(0.037,(0.029,(0.031,(0.023,(0.062,
0.164)0.169)0.229)0.219)0.259)
P(Diff>0)0.8940.9160.9950.992>0.999
P(Diff>0.15)0.0440.0550.3450.2800.588
P(Diff>0.2)0.0040.0050.0830.0560.221
Note:Placebo(N=102):n=95
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.
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Table30.2
BayesianAnalysisofWeightedMeanChangefromBaselineinPulseRate(beats/min)(04hours)onDay28
3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)
BayesianAnalysisAssuming
NoninformativePrior
n8491889397
PosteriorMeanDifference(SD)0.1(1.13)0.9(1.10)1.0(1.11)0.4(1.10)2.2(1.10)
95%CredibleInterval(2.1,2.3)(3.1,1.2)(3.1,1.2)(1.7,2.6)(0.0,4.3)
P(Diff>6)<0.001<0.001<0.001<0.001<0.001
Note:Placebo(N=102):n=87
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.
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Table30.3
BayesianAnalysisofMaximumIncreasefromBaselineinPulseRate(beats/min)(04hours)onDay28
3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)
BayesianAnalysisAssuming
NoninformativePrior
n8591889398
PosteriorMeanDifference(SD)0.1(1.27)0.3(1.24)0.1(1.25)1.0(1.23)2.7(1.23)
95%CredibleInterval(2.4,2.6)(2.7,2.1)(2.6,2.3)(1.4,3.4)(0.3,5.1)
P(Diff>10)<0.001<0.001<0.001<0.001<0.001
Note:Placebo(N=102):n=87
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.
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Table30.4
BayesianAnalysisofMaximumIncreasefromBaselineinGlucose(mmol/L)(04hours)onDay28
3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)
BayesianAnalysisAssuming
NoninformativePrior
n8390879394
PosteriorMeanDifference(SD)0.06(0.163)0.05(0.159)0.06(0.160)0.20(0.157)0.20(0.157)
95%CredibleInterval(0.38,0.26)(0.27,0.36)(0.26,0.37)(0.11,0.50)(0.11,0.50)
P(Diff>1.5)<0.001<0.001<0.001<0.001<0.001
Note:Placebo(N=102):n=85
Note:Analysisadjustedforbaseline(predosemeasurementonDay1),country,sex,age,stratumandtreatment.
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Table30.5
BayesianAnalysisofMaximumDecreasefromBaselineinFastingPotassium(mmol/L)(04hours)onDay28
3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)
BayesianAnalysisAssuming
NoninformativePrior
n7884848690
PosteriorMeanDifference(SD)0.05(0.053)0.14(0.052)0.09(0.052)0.07(0.052)0.14(0.052)
95%CredibleInterval(0.16,0.05)(0.25,0.04)(0.19,0.01)(0.17,0.03)(0.25,0.04)
P(Diff<0.3)<0.0010.001<0.001<0.0010.002
Note:Placebo(N=102):n=77
Note:Analysisadjustedforbaseline(predosemeasurementonDay1),country,sex,age,stratumandtreatment.
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3.2.
Figures
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Figure 6.101 Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum .
Figure 7.104 PM Minus AM PEF (L/min) Over the Screening and Treatment
Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.105 Mean Number of Puffs of Rescue Medication Per Day, by Stratum . . .
Figure 7.106 Box Plot of Trough % Predicted FEV1 (LOCF) at Day 28, by %
Predicted FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
13
14
Figure 7.110 Adjusted Means of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 - Intent-to-Treat Without Regression Line . . . . . . . . . . . . . . .
15
16
21
23
24
25
Table 7.103 Statistical Analysis of Change from Baseline in Day 1 Trough FEV1
(L) Intent-to-Treat (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .
26
Table 7.104 Summary of Number of Puffs of Rescue Medication, Day 1 and Last
Clinic Visit (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
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Table 7.107 Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) Subset of Subjects who had the 6-12 hour time points measured Per
Protocol (Per Protocol Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
31
32
Page 1 of 2
Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.101
Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum
Stratum=1: >=40% - <=65%
30
20
CONFIDENTIAL
25
15
10
1 Week
2 Weeks
3 Weeks
4 Weeks
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy
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Randomisation
Page 2 of 2
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Population: Intent-to-Treat
Figure 6.101
Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum
Stratum=2: >65% - <=90%
30
20
CONFIDENTIAL
25
15
10
1 Week
2 Weeks
3 Weeks
4 Weeks
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy
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Page 1 of 1
Figure 7.101
Adjusted Treatment Differences of Change from Baseline in PM PEF (L/min)
Days 1-28, by %Predicted FEV1 Stratum
60
55
45
40
35
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50
30
25
20
15
10
-5
3mcg
6.25mcg
Stratum
12.5mcg
>=40% - <=65%
25mcg
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
50mcg
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.102
Adjusted Treatment Differences of Change from Baseline in AM PEF (L/min)
Days 1-28, by %Predicted FEV1 Stratum
60
55
45
40
35
CONFIDENTIAL
50
30
25
20
15
10
-5
3mcg
6.25mcg
Stratum
12.5mcg
>=40% - <=65%
25mcg
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
50mcg
YM2008/00019/00
B2C109575
Page 1 of 1
Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.103
Mean Number of Puffs of Rescue Medication Per Day
5
CONFIDENTIAL
0
-7
14
21
Days
Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
-14
Page 1 of 1
Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.104
PM Minus AM PEF (L/min) Over the Screening and Treatment Periods
60
50
30
CONFIDENTIAL
40
20
10
-10
-7
14
21
Days
Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
-14
Page 1 of 2
Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.105
Mean Number of Puffs of Rescue Medication Per Day, by Stratum
Stratum=1: >=40% - <=65%
5
CONFIDENTIAL
0
-7
14
21
Days
Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
-14
Page 2 of 2
Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.105
Mean Number of Puffs of Rescue Medication Per Day, by Stratum
Stratum=2: >65% - <=90%
5
CONFIDENTIAL
10
0
-7
14
21
Days
Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
28
YM2008/00019/00
B2C109575
-14
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Figure 7.106
Box Plot of Trough % Predicted FEV1 (LOCF) at Day 28, by % Predicted FEV1 Stratum
Stratum=1: >=40% - <=65%
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal.
For further information please see the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
11
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.107
Adjusted Treatment Differences of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Days 1-28, by %Predicted FEV1 Stratum
40
35
25
CONFIDENTIAL
13
30
20
15
10
-5
3mcg
6.25mcg
Stratum
12.5mcg
>=40% - <=65%
25mcg
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
50mcg
YM2008/00019/00
B2C109575
-10
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.108
Adjusted Treatment Differences of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Days 1-28, by %Predicted FEV1 Stratum
50
45
35
30
CONFIDENTIAL
14
40
25
20
15
10
-10
3mcg
6.25mcg
Stratum
12.5mcg
>=40% - <=65%
25mcg
>65% - <=90%
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
50mcg
YM2008/00019/00
B2C109575
-5
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Figure 7.110
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 - Intent-to-Treat
Without Regression Line
0.4
CONFIDENTIAL
15
0.3
0.2
0.1
12.5mcg
25mcg
Treatment
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.
50mcg
YM2008/00019/00
B2C109575
0.0
Protocol: B2C109575
Population: Total
Page 1 of 5
Table 6.101
Summary of Investigator Performance
Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Argentina
Any Investigator
16
Canada
Any Investigator
(67%)
(88%)
(56%)
(60%)
(56%)
(57%)
36
15
5
3
9
4
(67%)
(88%)
(56%)
(60%)
(56%)
(57%)
34
14
4
3
9
4
(63%)
(82%)
(44%)
(60%)
(56%)
(57%)
4
3
1
0
0
0
17
12
5
7
6
1
(41%)
(50%)
(20%)
7
6
1
(41%)
(50%)
(20%)
7
6
1
(41%)
(50%)
(20%)
0
0
0
92
13
4
27
2
5
10
3
28
25
3
1
12
1
2
2
1
3
(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)
25
3
1
12
1
2
2
1
3
(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)
25
3
1
12
1
2
2
1
3
(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)
1
0
0
0
0
0
0
0
1
11
2
9
7
0
7
(64%)
7
0
7
(64%)
7
0
7
(64%)
0
0
0
(78%)
(78%)
(78%)
(7%)
(18%)
(11%)
29
12
5
3
6
3
5.9
5
4.9
2.6
4.1
3.7
9.2
3.4
1.9
1.9
3.9
1.9
(29%) 11.9
(33%) 9.7
(20%) 6.1
1.4
1.2
0.8
22
3
1
10
1
1
2
1
3
(24%)
(23%)
(25%)
(37%)
(50%)
(20%)
(20%)
(33%)
(11%)
24
16.1
9
21.1
0.6
13.9
16.6
4
19.1
3.8
0.8
0.4
1.3
3.5
0.4
0.6
0.8
1.5
7
0
7
(64%)
2.3
1
2.3
4.8
2
3.9
5
4
1
(1%)
(4%)
(54%)
(71%)
(56%)
(60%)
(38%)
(43%)
(78%)
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.
YM2008/00019/00
B2C109575
Chile
Any Investigator
36
15
5
3
9
4
CONFIDENTIAL
Belgium
Any Investigator
54
17
9
5
16
7
Protocol: B2C109575
Population: Total
Page 2 of 5
Table 6.101
Summary of Investigator Performance
Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------France
Any Investigator
17
Korea
Any Investigator
(52%)
(45%)
(71%)
14
0
4
10
(48%)
97
12
18
17
27
3
4
5
11
65 (67%)
9 (75%)
15 (83%)
17 (100%)
12 (44%)
0
2 (50%)
2 (40%)
8 (73%)
63
8
15
16
12
0
2
2
8
(65%)
(67%)
(83%)
(94%)
(44%)
41
26
15
23
11
12
(56%)
(42%)
(80%)
55
9
30
16
21
8
4
9
(38%)
(89%)
(13%)
(56%)
(36%)
(71%)
13
0
4
9
(45%)
(36%)
(64%)
(61%)
(67%)
(78%)
(94%)
(44%)
(50%)
(40%)
(73%)
59
8
14
16
12
0
2
1
6
23
11
12
(56%)
(42%)
(80%)
19
7
3
9
(35%)
(78%)
(10%)
(56%)
1
0
0
1
(3%)
(7%)
(8%)
(8%)
(11%)
13
0
4
9
(45%) 13.3
5.4
(36%) 5.3
(64%) 13.3
(58%)
(58%)
(83%)
(82%)
(41%)
(50%)
(20%)
(55%)
8
1
2
0
2
0
0
1
2
(20%)
(18%)
56
7
15
14
11
0
2
0
7
21
9
12
(51%)
(35%)
(80%)
3
2
1
(7%)
(8%)
(7%)
22
11
11
(54%)
(42%)
(73%)
9.7
8.6
9
4.2
3
1.7
19
7
3
9
(35%)
(78%)
(10%)
(56%)
1
1
0
0
(2%)
(11%)
18
6
3
9
(33%) 20.4
(67%) 7.1
(10%) 20.4
(56%) 11.1
2.7
1.3
1.5
1.4
(7%)
19
10
14.1
18
1.9
0.4
(50%) 6.4
11.1
(64%) 13.1
2.2
0.7
2.1
1.1
Peru
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.
5.1
1.2
1.3
0.9
14.5
7
0.6
0.4
0.8
YM2008/00019/00
B2C109575
Netherlands
Any Investigator
15
0
5
10
CONFIDENTIAL
Germany
Any Investigator
29
4
11
14
Protocol: B2C109575
Population: Total
Page 3 of 5
Table 6.101
Summary of Investigator Performance
Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Any Investigator
18
Poland
Any Investigator
Russian Federation
Any Investigator
21
1
7
13
(58%)
(20%)
(70%)
(62%)
21
1
7
13
(58%)
(20%)
(70%)
(62%)
21
1
7
13
(58%)
(20%)
(70%)
(62%)
1
0
1
0
23
12
11
8
6
2
(35%)
(50%)
(18%)
8
6
2
(35%)
(50%)
(18%)
7
6
1
(30%)
(50%)
(9%)
1
0
1
102
7
15
2
43
35
(10%)
(4%)
(9%)
81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)
81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)
81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)
5
1
1
0
1
2
(5%)
(14%)
(7%)
41
8
3
6
1
4
16
3
41
8
3
6
1
4
16
3
40
8
2
6
1
4
16
3
3
1
1
1
0
0
0
0
(4%)
(10%)
(14%)
(7%)
(55%)
(80%)
(43%)
(43%)
(13%)
(36%)
(94%)
(43%)
(55%)
(80%)
(43%)
(43%)
(13%)
(36%)
(94%)
(43%)
(54%)
(80%)
(29%)
(43%)
(13%)
(36%)
(94%)
(43%)
(2%)
(6%)
18
1
6
11
(50%)
(20%)
(60%)
(52%)
5.1
4.9
2.4
4.7
7
1
4.1
4.5
6
5
1
(26%)
(42%)
(9%)
5.3
2.3
5.3
4.4
5.3
2.1
72 (71%) 16.4
1 (14%) 0.1
9 (60%) 14.3
2 (100%) 4.4
29 (67%) 13
31 (89%) 4
6.2
49
1.1
0.5
3.3
8.8
38
7
3
5
1
4
15
3
(51%) 11.1
(70%) 5.9
(43%) 4.9
(36%) 3
(13%) 8.9
(36%) 8.3
(88%) 3.6
(43%) 5.4
South Africa
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.
6.6
1.7
1.4
4.7
0.9
1.3
4.8
1.3
YM2008/00019/00
B2C109575
74
10
7
14
8
11
17
7
(3%)
CONFIDENTIAL
Philippines
Any Investigator
36
5
10
21
Protocol: B2C109575
Population: Total
Page 4 of 5
Table 6.101
Summary of Investigator Performance
Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Any Investigator
19
Thailand
Any Investigator
United States
Any Investigator
10
1
7
0
2
(32%)
(25%)
(41%)
27
16
11
(32%)
(25%)
(41%)
(50%)
10
1
7
0
2
15
7
8
(56%)
(44%)
(73%)
31
22
9
18
14
4
(58%)
(64%)
(44%)
420
7
15
5
6
8
5
4
4
5
11
14
221
6
8
1
3
2
3
2
1
3
5
10
15
7
8
(56%)
(44%)
(73%)
18
14
4
(58%)
(64%)
(44%)
(53%) 219
(86%)
6
(53%)
8
(20%)
1
(50%)
3
(25%)
2
(60%)
3
(50%)
2
(25%)
1
(60%)
3
(45%)
5
(71%) 10
(50%)
0
0
0
0
0
8
1
6
0
1
15
7
8
(56%)
(44%)
(73%)
0
0
0
17
13
4
(55%)
(59%)
(44%)
2
2
0
(49%) 15
(86%) 0
(53%) 0
(20%) 0
(50%) 0
(25%) 0
(60%) 0
2
1
(40%) 1
(45%) 0
(71%) 1
(52%) 207
(86%)
6
(53%)
8
(20%)
1
(50%)
3
(25%)
2
(60%)
3
(50%)
0
(25%)
0
(60%)
2
(45%)
5
(71%) 10
3.3
1.3
3.3
1.1
0.4
9.4
3.1
5.2
5.3
9.3
15
7
8
(56%) 14.3
(44%) 13.3
(73%) 10.4
1.9
1.2
1.1
(6%)
(9%)
16
12
4
(52%)
(55%)
(44%)
7
5
9
(4%)
194
6
6
1
3
2
3
2
0
2
4
10
(46%)
(86%)
(40%)
(20%)
(50%)
(25%)
(60%)
(50%)
(50%)
(25%)
(20%)
(7%)
(26%)
(25%)
(35%)
(25%)
4.4
4.4
1
26
5.7
13.6
8.9
21
16.9
14.3
4.1
14.9
(40%) 8
(36%) 15.6
(71%) 21.4
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.
16.2
1.2
1.1
0.6
0.3
0.5
0.4
1
0.3
0.6
0.7
0.7
YM2008/00019/00
B2C109575
(32%)
(25%)
(41%)
(50%)
10
1
7
0
2
CONFIDENTIAL
Sweden
Any Investigator
31
4
17
6
4
Protocol: B2C109575
Population: Total
Page 5 of 5
Table 6.101
Summary of Investigator Performance
Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------8
9
7
2
2
2
17
13
14
17
4
7
6
22
9
1
8
17
12
(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(74%)
(72%)
(70%)
(77%)
(44%)
(28%)
(43%)
(65%)
(75%)
(14%)
(62%)
(57%)
(43%)
8
9
7
2
2
2
17
13
14
17
4
7
6
22
9
1
7
16
12
(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(74%)
(72%)
(70%)
(77%)
(44%)
(28%)
(43%)
(65%)
(75%)
(14%)
(54%)
(53%)
(43%)
8
9
7
2
2
2
16
11
13
17
4
5
6
22
9
1
7
15
11
(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(70%)
(61%)
(65%)
(77%)
(44%)
(20%)
(43%)
(65%)
(75%)
(14%)
(54%)
(50%)
(39%)
0
0
0
0
0
0
1
2
1
1
0
2
0
0
0
0
0
1
2
(4%)
(11%)
(5%)
(5%)
(8%)
(3%)
(7%)
7
9
7
2
2
2
15
12
13
16
4
6
5
18
9
0
5
15
8
(30%)
(53%)
(78%)
(25%)
(14%)
(20%)
(65%)
(67%)
(65%)
(73%)
(44%)
(24%)
(36%)
(53%)
(75%)
16.3
17.6
6.4
12.6
11
13
14.1
17.4
23.7
24
5.3
22.4
11.7
12.9
8.7
2.4
(38%) 17.4
(50%) 21.6
(29%) 18.3
YM2008/00019/00
B2C109575
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.
1.4
1
1.4
0.6
1.3
0.8
1.6
1
0.8
0.9
1.7
1.1
1.2
2.6
1.4
2.9
0.7
1.4
1.5
CONFIDENTIAL
20
23
17
9
8
14
10
23
18
20
22
9
25
14
34
12
7
13
30
28
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 6.102
Summary of Reversibility at Screening by Actual Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------Percent Reversibility
n
44
46
43
42
47
46
FEV1 (%)
Mean
31.1
26.4
27.6
27.4
28.6
29.7
SD
17.49
15.32
14.55
13.29
23.08
19.32
Median
24.7
21.2
26.4
23.7
20.1
26.2
Min.
12
2
10
12
12
-12
Max.
86
76
82
74
123
102
21
n
44
Mean
542.8
SD
319.85
Median 433.5
Min.
202
Max.
1552
46
447.4
270.44
338.0
29
1317
43
489.9
213.72
432.0
207
936
42
522.3
258.56
478.0
201
1501
47
520.4
408.61
383.0
200
2207
46
530.4
305.66
439.0
-229
1427
CONFIDENTIAL
Absolute Reversibility
FEV1 (mL)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 6.102
Summary of Reversibility at Screening by Actual Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------Percent Reversibility
n
58
55
58
58
54
56
FEV1 (%)
Mean
23.3
22.4
25.4
23.7
26.4
23.6
SD
12.70
11.49
16.04
17.96
18.63
10.78
Median
18.7
17.7
21.1
16.8
19.4
20.4
Min.
7
12
6
12
12
13
Max.
67
70
100
125
114
72
22
n
58
Mean
565.2
SD
286.98
Median 457.0
Min.
164
Max.
1697
55
576.7
259.80
521.0
215
1305
58
616.7
328.62
520.0
148
1564
58
547.7
296.61
464.0
209
1499
54
557.4
267.15
465.0
243
1277
56
542.3
203.73
497.5
257
1028
CONFIDENTIAL
Absolute Reversibility
FEV1 (mL)
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 6.104
Summary of Adolescent Subjects
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Age (y)
n
7
2
2
7
5
4
27
12-13 years
1 (14%)
0
0
3 (43%)
1 (20%)
1 (25%)
6 (22%)
14-15 years
6 (86%)
1 (50%)
0
3 (43%)
1 (20%)
2 (50%)
13 (48%)
16-17 years
0
1 (50%)
2 (100%)
1 (14%)
3 (60%)
1 (25%)
8 (30%)
CONFIDENTIAL
23
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.101
Statistical Analysis of Change from Baseline in PM PEF (L/min) by % Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
44
45
43
40
47
46
LS Mean
374.7
391.8
402.4
414.5
414.0
417.2
LS Mean Change
-3.1(5.92)
13.9(5.88)
24.6(5.96)
36.7(6.15)
36.1(5.70)
39.4(5.87)
(SE)
24
17.0
(0.9,33.2)
55
380.9
3.1(5.20)
54
392.1
14.2(5.39)
11.2
(-3.4,25.7)
27.7
(11.5,43.9)
58
402.3
24.4(5.18)
21.4
(7.1,35.7)
39.8
(23.1,56.5)
58
401.3
23.4(5.13)
20.4
(6.2,34.6)
39.2
(23.3,55.1)
54
410.1
32.2(5.33)
29.1
(14.7,43.6)
42.5
(26.4,58.6)
56
415.4
37.6(5.15)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
34.5
(20.2,48.9)
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.102
Statistical Analysis of Change from Baseline in AM PEF (L/min) by % Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
45
43
40
47
46
LS Mean
365.0
379.9
389.5
397.7
402.2
403.2
LS Mean Change
2.3(5.72)
17.1(5.58)
26.7(5.67)
34.9(5.84)
39.4(5.42)
40.5(5.57)
(SE)
25
14.8
(-0.6,30.3)
55
364.3
1.6(4.95)
54
382.7
20.0(5.11)
18.4
(4.6,32.2)
24.4
(8.9,40.0)
58
389.6
26.9(4.94)
25.3
(11.7,38.9)
32.7
(16.7,48.6)
58
396.5
33.7(4.88)
32.2
(18.7,45.6)
37.1
(21.9,52.4)
54
399.7
37.0(5.07)
35.4
(21.7,49.1)
38.2
(22.8,53.6)
56
409.5
46.8(4.90)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
45.2
(31.5,58.8)
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.103
Statistical Analysis of Change from Baseline in Day 1 Trough FEV1 (L)
Intent-to-Treat
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
101
101
101
99
100
101
LS Mean
2.415
2.499
2.448
2.503
2.551
2.556
LS Mean Change
0.173(0.032)
0.257(0.032)
0.207(0.031)
0.262(0.032)
0.310(0.032)
0.314(0.031)
(SE)
0.084
0.034
0.088
(-0.004,0.172) (-0.054,0.121) (0.000,0.176)
0.062
0.449
0.049
0.136
(0.049,0.224)
0.002
0.141
(0.053,0.229)
0.002
26
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
p-value
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 2
Table 7.104
Summary of Number of Puffs of Rescue Medication, Day 1 and Last Clinic Visit
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
Nighttime
No puffs
44 (43%)
39 (39%)
38 (38%)
40 (40%)
37 (37%)
39 (38%)
1 or more puffs
57 (56%)
61 (60%)
61 (60%)
58 (58%)
62 (61%)
63 (62%)
Missing
1 (<1%)
1 (<1%)
2 (2%)
2 (2%)
2 (2%)
0
36 (35%)
50 (49%)
16 (16%)
41 (41%)
44 (44%)
16 (16%)
33 (33%)
47 (47%)
21 (21%)
36 (36%)
51 (51%)
13 (13%)
33 (33%)
47 (47%)
21 (21%)
41 (40%)
45 (44%)
16 (16%)
24 Hour
No puffs
1 or more puffs
Missing
22 (22%)
71 (70%)
9 (9%)
20 (20%)
76 (75%)
5 (5%)
18 (18%)
77 (76%)
6 (6%)
16 (16%)
79 (79%)
5 (5%)
15 (15%)
79 (78%)
7 (7%)
19 (19%)
77 (75%)
6 (6%)
No puffs
1 or more puffs
Missing
39 (38%)
30 (29%)
33 (32%)
47 (47%)
16 (16%)
38 (38%)
56 (55%)
15 (15%)
30 (30%)
42 (42%)
18 (18%)
40 (40%)
62 (61%)
14 (14%)
25 (25%)
57 (56%)
19 (19%)
26 (25%)
Daytime
No puffs
1 or more puffs
Missing
26 (25%)
39 (38%)
37 (36%)
25 (25%)
35 (35%)
41 (41%)
28 (28%)
31 (31%)
42 (42%)
18 (18%)
37 (37%)
45 (45%)
29 (29%)
30 (30%)
42 (42%)
30 (29%)
31 (30%)
41 (40%)
24 Hour
No puffs
1 or more puffs
Missing
18 (18%)
51 (50%)
33 (32%)
20 (20%)
40 (40%)
41 (41%)
20 (20%)
37 (37%)
44 (44%)
10 (10%)
45 (45%)
45 (45%)
26 (26%)
35 (35%)
40 (40%)
22 (22%)
42 (41%)
38 (37%)
No puffs
1 or more puffs
Missing
37 (36%)
24 (24%)
41 (40%)
39 (39%)
25 (25%)
37 (37%)
49 (49%)
9 (9%)
43 (43%)
45 (45%)
12 (12%)
43 (43%)
49 (49%)
14 (14%)
38 (38%)
50 (49%)
12 (12%)
40 (39%)
Day 2
Nighttime
YM2008/00019/00
B2C109575
No puffs
1 or more puffs
Missing
CONFIDENTIAL
27
Daytime
Protocol: B2C109575
Population: Intent-to-Treat
Page 2 of 2
Table 7.104
Summary of Number of Puffs of Rescue Medication, Day 1 and Last Clinic Visit
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Daytime
No puffs
30 (29%)
28 (28%)
24 (24%)
25 (25%)
33 (33%)
29 (28%)
1 or more puffs
26 (25%)
35 (35%)
20 (20%)
32 (32%)
21 (21%)
20 (20%)
Missing
46 (45%)
38 (38%)
57 (56%)
43 (43%)
47 (47%)
53 (52%)
24 Hour
18 (18%)
39 (38%)
45 (44%)
17 (17%)
40 (40%)
44 (44%)
16 (16%)
25 (25%)
60 (59%)
20 (20%)
38 (38%)
42 (42%)
28 (28%)
27 (27%)
46 (46%)
16 (16%)
29 (28%)
57 (56%)
No puffs
1 or more puffs
Missing
37 (36%)
25 (25%)
40 (39%)
45 (45%)
25 (25%)
31 (31%)
38 (38%)
25 (25%)
38 (38%)
51 (51%)
25 (25%)
24 (24%)
55 (54%)
17 (17%)
29 (29%)
44 (43%)
28 (27%)
30 (29%)
Daytime
No puffs
1 or more puffs
Missing
27 (26%)
38 (37%)
37 (36%)
33 (33%)
40 (40%)
28 (28%)
31 (31%)
34 (34%)
36 (36%)
40 (40%)
41 (41%)
19 (19%)
46 (46%)
28 (28%)
27 (27%)
46 (45%)
33 (32%)
23 (23%)
24 Hour
No puffs
1 or more puffs
Missing
21 (21%)
43 (42%)
38 (37%)
26 (26%)
43 (43%)
32 (32%)
24 (24%)
41 (41%)
36 (36%)
35 (35%)
44 (44%)
21 (21%)
38 (38%)
34 (34%)
29 (29%)
33 (32%)
40 (39%)
29 (28%)
28
YM2008/00019/00
B2C109575
CONFIDENTIAL
No puffs
1 or more puffs
Missing
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.106
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (Day 28, 22-24hrs)
by % Predicted FEV1 Stratum
Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------->=40%-<=65% 22 hours 18 / 39 (46%) 17 / 35 (49%) 17 / 34 (50%) 17 / 35 (49%) 27 / 43 (63%) 29 / 39 (74%)
23 hours 15 / 39 (38%) 15 / 35 (43%) 16 / 34 (47%) 18 / 35 (51%) 30 / 43 (70%) 29 / 42 (69%)
24 hours 14 / 38 (37%) 13 / 35 (37%) 19 / 35 (54%) 21 / 36 (58%) 32 / 43 (74%) 28 / 42 (67%)
>65%-<=90%
29
CONFIDENTIAL
22 hours
23 hours
24 hours
YM2008/00019/00
B2C109575
Protocol: B2C109575
Population: Per Protocol
Page 1 of 1
Table 7.107
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Subset of Subjects who had the 6-12 hour time points measured
Per Protocol
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-----------------------------------------------------------------------------------------------------------n
61
61
63
69
57
56
LS Mean
2.428
2.529
2.519
2.533
2.608
2.552
LS Mean Change
0.161(0.044)
0.262(0.045)
0.252(0.044)
0.266(0.042)
0.341(0.046)
0.285(0.047)
(SE)
0.100
0.091
0.105
0.180
(-0.025,0.226) (-0.032,0.213) (-0.016,0.225) (0.054,0.305)
0.124
(-0.003,0.251)
30
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.108
Statistical Analysis of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
by % Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
45
43
40
47
46
LS Mean
23.0
32.1
30.9
40.8
45.2
38.8
LS Mean Change
12.6(5.04)
21.7(4.89)
20.5(5.02)
30.4(5.15)
34.8(4.78)
28.5(4.83)
(SE)
31
9.1
(-4.6,22.8)
55
25.7
15.3(4.39)
54
33.7
23.4(4.44)
8.1
(-4.1,20.2)
7.9
(-5.8,21.7)
58
36.3
25.9(4.31)
10.6
(-1.4,22.6)
17.8
(3.6,31.9)
58
34.9
24.5(4.30)
9.2
(-2.7,21.1)
22.2
(8.7,35.7)
54
48.1
37.7(4.46)
22.4
(10.2,34.5)
15.8
(2.2,29.5)
56
45.7
35.4(4.33)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
20.0
(7.9,32.2)
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Protocol: B2C109575
Population: Intent-to-Treat
Page 1 of 1
Table 7.109
Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
by % Predicted FEV1 Stratum
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
44
45
43
40
47
46
LS Mean
24.3
33.8
33.1
40.1
57.0
41.6
LS Mean Change
11.2(5.10)
20.7(5.01)
20.1(5.12)
27.1(5.27)
43.9(4.89)
28.5(4.94)
(SE)
32
9.5
(-4.4,23.4)
55
30.9
17.9(4.51)
54
42.9
29.9(4.56)
12.0
(-0.5,24.4)
8.9
(-5.2,22.9)
58
45.9
32.8(4.40)
15.0
(2.7,27.3)
15.9
(1.5,30.3)
58
44.8
31.8(4.40)
13.9
(1.6,26.1)
32.7
(19.0,46.5)
54
55.6
42.6(4.56)
24.7
(12.3,37.1)
17.3
(3.4,31.2)
56
51.5
38.4(4.44)
CONFIDENTIAL
Column vs Placebo
Difference
95% C.I.
20.6
(8.2,32.9)
YM2008/00019/00
B2C109575
Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject