Nej Mo A 1505180

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Eluxadoline for Irritable Bowel Syndrome

with Diarrhea
AnthonyJ. Lembo, M.D., BrianE. Lacy, M.D., Ph.D., MarcJ. Zuckerman, M.D.,
Ron Schey, M.D., LeonardS. Dove, Ph.D., DavidA. Andrae, Ph.D.,
J.Michael Davenport, Ph.D., Gail McIntyre, Ph.D., Rocio Lopez, Ph.D.,
Lisa Turner, R.Ph., and PaulS. Covington, M.D.
A BS T R AC T
BACKGROUND
From Harvard Medical School, Boston
(A.J.L.); Geisel School of Medicine at
Dartmouth, Hanover, NH (B.E.L.); Texas
Tech University Health Sciences Center,
El Paso (M.J.Z.); School of Medicine,
Temple University, Philadelphia (R.S.);
and Furiex Pharmaceuticals, Morrisville,
NC (L.S.D., D.A.A., J.M.D., G.M., R.L.,
L.T., P.S.C.). Address reprint requests to
Dr. Lembo at the Department of Medicine, Division of Gastroenterology, Harvard
Medical School, Beth Israel Deaconess
Medical Center, 330 Brookline Ave., Boston, MA 02115, or at
alembo@
bidmc
.harvard.edu.
N Engl J Med 2016;374:242-53.
DOI: 10.1056/NEJMoa1505180
Copyright 2016 Massachusetts Medical Society.
Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy
and safety of eluxadoline, a new oral agent with mixed opioid effects (- and
-opioid receptor agonist and -opioid receptor antagonist), in patients with IBS
with diarrhea.
METHODS
We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a
dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or
52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who
had a composite response of decrease in abdominal pain and improvement in stool
consistency on the same day for at least 50% of the days from weeks 1 through 12
and from weeks 1 through 26.
RESULTS
For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg)
than in the placebo group reached the primary end point (IBS-3001 trial, 23.9%
with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo;
P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively,
vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and
P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and
32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as
compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4%
and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis
developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666
patients in the safety population (0.3%).
CONCLUSIONS
Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea
in men and women, with sustained efficacy over 6 months in patients who received
the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of
Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and
NCT01553747, respectively.)
242
n engl j med 374;3nejm.org January 21, 2016
The New England Journal of Medicine

Downloaded from nejm.org on October 24, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
he irritable bowel syndrome (IBS)

with diarrhea is a common functional gastrointestinal disorder that is characterized
by recurring abdominal pain, bloating, and loose,
frequent stools in the absence of structural, inflammatory, or biochemical abnormalities. IBS
with diarrhea is associated with impairment in
health-related quality of life, places a considerable financial burden on society because of reduced work productivity, and increases the use of
health-related resources.1,2 IBS is the most frequent diagnosis in gastroenterology practices
and one of the most frequent diagnoses in primary care practices.3
Current treatment options for IBS with diarrhea are limited. Initial therapies include dietary
and lifestyle modifications along with antidiarrheal agents; these therapies are frequently unsuccessful. A subgroup of patients with IBS with
diarrhea may have a response to either rifaximin
or alosetron.4,5 Alosetron has been approved by the
Food and Drug Administration (FDA) only for
women with severe IBS with diarrhea who have
not had a response to conventional therapy, although subsequent data suggest efficacy in men.6,7
Opioid receptors (including -, -, and -opioid
receptors) in the enteric circuitry of the gastrointestinal tract play a role in regulating gastrointestinal motility, secretion, and visceral sensation. The mechanism of action of opioid agonists
is complex because of various receptor subtypes
and various sites of action (central sites vs. peripheral sites), but these agents are generally mediated through inhibitory effects that interrupt
neuroneuronal and neuroeffector transmission.8
The effects of activation of -opioid receptors on
gastrointestinal motility and secretion have been
studied more extensively than the effects of activation or modulation of -opioid receptors and
-opioid receptors.
The -opioid receptors are expressed in overlapping neuronal populations, and their agonists
have been shown to inhibit effects on gastrointestinal circular muscle.9 Antagonism of -opioid
receptors has been shown to functionally counteract the inhibiting effects of -opioid receptor
agonists on gastrointestinal transit and increase
-opioid receptormediated central analgesia.10-12
Eluxadoline (Viberzi, Allergan) is a peripherally acting mixed -opioid receptor agonistopioid receptor antagonist and -opioid receptor
agonist with minimal oral bioavailability.12 Nonclinical studies have shown that, unlike selective
-opioid receptor agonists, eluxadoline reduces
visceral hypersensitivity without completely disrupting intestinal motility. These data suggest
that peripheral -opioid receptor antagonism may
reduce -opioid receptormediated constipation
and, similar to its documented effects on central
analgesia, enhance -opioid receptormediated
peripheral analgesia.12
In a phase 2 study, a significantly greater
proportion of patients who received eluxadoline
at a dose of 100 mg or 200 mg twice daily than
of patients who received placebo reported reductions in their symptoms of IBS with diarrhea.13
Since the 200-mg twice-daily dose did not provide efficacy advantages over the 100-mg dose
and resulted in more adverse events, phase 3 trials
included a group of patients who received a dose
of 100 mg twice daily and a group of patients
who received 75 mg twice daily. The objectives
of these current trials were to evaluate the clinical response of patients with IBS with diarrhea to
eluxadoline, as compared with placebo, through
26 weeks and to evaluate the safety of eluxadoline up to 52 weeks.
Me thods
Patients
We enrolled patients who were 18 to 80 years of

age and who had IBS with diarrhea (as assessed
according to the Rome III diagnostic criteria for
IBS).14 Enrolled patients were included if they
recorded, during the week before randomization, an average score for their worst abdominal
pain as greater than 3.0 (on a scale of 0 to 10,
with 0 indicating no pain and 10 the worst
imaginable pain), an average score for stool consistency of 5.5 or more on the Bristol Stool Form
Scale (which ranges from 1 to 7, with 1 indicating hard stool and 7 indicating watery diarrhea),
a score of 5 or higher on the Bristol Stool Form
Scale for at least 5 days, and an average IBS-D
global symptom score for symptoms of IBS with
diarrhea of 2.0 or more (on a scale of 0 to 4, with
0 indicating no symptoms of IBS with diarrhea
and 4 very severe symptoms of IBS with diarrhea).
Patients were excluded if they had a history of
inflammatory bowel disease or celiac disease,
abnormal thyroid function, a history of alcohol

243
The
abuse15 or binge drinking,16 pancreatitis, sphincter

of Oddi dysfunction, post-cholecystectomy biliary
pain, cholecystitis within the past 6 months, or a
known allergy to opioids, or if they were pregnant
or breast-feeding or were receiving antidiarrheal,
antispasmodic, or narcotic drugs. Patients who
were receiving antidepressant medications were
eligible to participate in the study, provided that
dosing had been stable for 12 weeks or longer
before enrollment.
Study Design
We conducted two randomized, double-blind,

placebo-controlled, parallel-group, multicenter
studies from May 29, 2012, through July 29,
2014. A total of 295 centers participated in the
IBS-3001 trial (269 in the United States, 9 in
Canada, and 17 in the United Kingdom). This
total included 40 IBS-3002 sites that agreed to
participate in the IBS-3001 trial once enrollment
was completed in the IBS-3002 trial. From May
29, 2012, through January 9, 2014, a total of 261
centers participated in the IBS-3002 trial (241 in
the United States, 10 in Canada, and 10 in the
United Kingdom).
The studies included a pretreatment period
(a prescreening period of up to 1 week and a
screening period of up to 3 weeks) and a 26-week
double-blind, placebo-controlled study period for
collection of efficacy data. This period was followed by either 26 additional weeks of doubleblind treatment for safety assessment only and a
2-week post-treatment follow-up period (IBS-3001)
or a 4-week, single-blind period of placebo withdrawal (i.e., regardless of original randomization, all patients received single-blind placebo to
assess for rebound worsening of symptoms)
(IBS-3002) (Fig. S1 in the Supplementary Appendix, available with the full text of this article at
NEJM.org).
Patients who met the inclusion criteria and
did not meet exclusion criteria were randomly
assigned to receive oral tablets of eluxadoline (at a
dose of 75 mg or 100 mg) or placebo twice daily.
Randomization schedules were generated by a
statistician who was aware of the patient assignments and who was not part of the operational
statistical team (the members of which were
unaware of the patient assignments), and were
implemented centrally by an interactive voiceresponse system. The interactive voice-response
system also served as the electronic patient diary
244
of
m e dic i n e
and collected patient-reported daily symptoms of

IBS with diarrhea, bowel functioning, and use
of loperamide rescue treatment.
During the first 26 weeks of the IBS-3001
trial and the first 30 weeks of the IBS-3002 trial,
the following assessments by patients were recorded daily: the score for the worst abdominal
pain, the extent of discomfort and bloating (each
scored on a scale of 0 to 10, with 0 indicating no
symptoms and 10 indicating the worst imaginable symptoms), the stool consistency score, the
number of bowel movements and whether they
were associated with urgency or fecal incontinence, and the IBS-D global symptom score. In
addition, adequate relief of IBS symptoms was
assessed weekly.
In both studies, patient visits occurred at
weeks 2, 4, 8, 12, 18, and 26. In addition, patient
visits occurred at weeks 36, 44, and 52 in the
IBS-3001 trial and at week 30 in the IBS-3002
trial. Quality of life was assessed with the use of
the 34-item Irritable Bowel Syndrome Quality of
Life (IBS-QOL) questionnaire (total scores range
from 0 to 100, with higher scores indicating better quality of life) on day 1, at week 4, and at all
subsequent visits through week 52.
Rescue medication was not allowed during the
screening period; however, loperamide was allowed as needed during the double-blind period
(at a dose of 2 mg every 6 hours, with no more
than four doses over the course of 24 hours
and no more than seven doses over the course of
48hours).
Study Oversight
The trials were designed by the first author and

the industry authors. Data collection was monitored by Pharmaceutical Product Development
(PPD), a contract research organization, under
the supervision of Furiex; data were analyzed by
PPD and the industry authors. All the authors
vouch for the completeness and veracity of the
data and analyses and for the fidelity of this report to the study protocols, available at NEJM.org.
The initial draft of the manuscript was written
by the first author and was reviewed by all the
authors. Editorial support was provided by a professional medical writer who was paid by the
sponsor. All the authors contributed to the revision of the manuscript, made the decision to
submit the manuscript for publication, and signed
a confidentiality agreement with the sponsor.

The institutional review board or ethics committee at each participating site approved the protocols, and all patients provided written informed
consent.
withdrawal. This scale includes 16 symptoms of

withdrawal, each of which has a possible score
of 0 to 4 for intensity (0 indicates no intensity,
1 minor intensity, 2 moderate intensity, 3 major
intensity, and 4 extreme intensity). An adjudicaEfficacy End Points
tion committee was established to review events
The primary efficacy end point was the propor- that were deemed to be suspicious for pancreatition of patients who had a composite response tis and cases of abdominal pain that were associ(i.e., patients who recorded on 50% of the days ated with elevated liver-enzyme levels.
a reduction of 30% from their average baseline
score for their worst abdominal pain and, on the Statistical Analysis
same days, a stool-consistency score of <5). If We estimated the sample size for each study asthe patient did not have a bowel movement, an suming that 14% of the patients in the placebo
improvement of at least 30% in the score for the group would meet the criteria for the primary
worst abdominal pain was sufficient for a re- end point and assuming a treatment effect of
sponse on that day. Responses were evaluated 10% for any eluxadoline group as compared with
over the initial 12 weeks (the FDA end point) and placebo. These calculations, which were based
26 weeks (the European Medicines Agency [EMA] on interactions with global regulatory authoriend point). A minimum of 60 diary-entry days ties, resulted in a sample of 375 patients per
from weeks 1 through 12 and 110 diary-entry group in each study. We calculated that with this
days from weeks 1 through 26 were required for sample size, the study would have approximately
the patient to be considered to have had a re- 90% power to detect the 10% treatment effect,
sponse.
with the use of a two-sided CochranMantel
Secondary end points included the following: Haenszel test, at a Bonferroni-adjusted alpha level
pain relief (reduction of 30% from baseline in of 0.025 to account for two active-treatmentthe score for the worst abdominal pain on 50% group comparisons with placebo, thereby mainof days), improvement in stool consistency (stool taining the family-wise alpha level. The treatconsistency score of <5, or the absence of a ment effect was assessed by means of pairwise
bowel movement if accompanied by an improve- CochranMantelHaenszel tests of eluxadoline
ment of 30% in the score for the worst ab- versus placebo with respect to the primary comdominal pain, on 50% of days), improvement posite response (weeks 1 through 12 and weeks
in the global symptom score (a score of 0 or 1, 1 through 26). No other adjustments for multior an improvement of 2 over the baseline score, plicity were made, since other analyses supported
on 50% of days), and adequate relief of IBS the primary analysis.
Patients were stratified according to the
symptoms (a response of yes on 50% of the
weeks to the following question: Over the past country in which they resided. Efficacy analyses
week, have you had adequate relief of your IBS involved the intention-to-treat population (i.e.,
symptoms?). In addition, the change from base- all patients who underwent randomization). No
line in the IBS-QOL questionnaire score was imputation for missing data was performed,
assessed. As a secondary end point, the compos- since the minimum compliance rules described
ite response was also evaluated over each 4-week above accounted for missing diary entries.
In addition, we performed a worst case
interval.
analysis that required 50% positive-response days
Safety
relative to the nominal days within the interval
Data on safety were collected for 26 weeks in the of interest in order for the patient to be considIBS-3002 trial and for 52 weeks in the IBS-3001 ered to have had a response (an absolute number
trial. Safety assessments included the assessment of 42 of 84 positive days from weeks 1 through
of adverse events and serious adverse events, 12 or 91 of 182 positive days from weeks 1
laboratory testing, 12-lead electrocardiography, through 26, regardless of adherence to reporting
and physical examinations. In addition, at the in the electronic diary). This approach effective
end of study, the Subjective Opiate Withdrawal ly imputed a nonresponse day for each day on
Scale17 was used to assess potential symptoms of which a diary entry was missing.

245
The
Efficacy analyses of pooled data from the two

studies were prospectively planned, with emphasis on relevant subgroups, including subgroups
defined according to age (<65 years vs. 65 years)
and sex. Additional prospective pooled analyses
included those that used alternative definitions
of pain response (40% and 50% reduction in
pain from baseline), analyses of the change from
baseline in raw symptom scores, and analyses of
the proportion of patients who had urgency-free
days. We generally used statistical approaches
(CochranMantelHaenszel tests) for pooled data
analyses that were identical to those used for the
individual studies. Potential treatment heterogeneities were evaluated by visual inspection of
forest plots of odds ratios for each subgroup.
The safety population included patients who
received at least one dose of either eluxadoline or
placebo. Safety end points were summarized according to study group with the use of descriptive statistics and included data for all patients
up to 52 weeks.
R e sult s
Patients
A total of 2428 patients (1282 in the IBS-3001

trial and 1146 in the IBS-3002 trial) were enrolled. One patient in the IBS-3001 trial received
a dose of eluxadoline but did not undergo randomization (Fig. S2 in the Supplementary Appendix). One patient in each trial underwent randomization twice (each tried to participate at
more than one study site). Therefore, the intention-to-treat population consisted of 2425 patients (1280 in the IBS-3001 trial and 1145 in the
IBS-3002 trial). Demographic and baseline characteristics were balanced across the groups and
studies (Table1).
Efficacy
From weeks 1 through 12, the proportion of

patients who were considered to have an FDA
end-point response was significantly greater
among those who received eluxadoline at a dose
of 75 mg or 100 mg twice daily than among
those who received placebo, both in the IBS-3001
trial (23.9% with the 75-mg dose and 25.1% with
the 100-mg dose vs. 17.1% with placebo; P=0.01
for the comparison of 75 mg with placebo and
P=0.004 for the comparison of 100 mg with
246
of
m e dic i n e
placebo) and in the IBS-3002 trial (28.9% and

29.6%, respectively, vs. 16.2%; P<0.001 for the
comparison of each dose of eluxadoline with
placebo) (Fig.1A). From weeks 1 through 26, the
proportions of patients who were considered to
have an EMA end-point response were 23.4% in
the 75-mg group and 29.3% in the 100-mg group,
versus 19.0% in the placebo group in the IBS3001 trial (P=0.11 for 75-mg comparison and
P<0.001 for the 100-mg comparison) and 30.4%
and 32.7%, respectively, versus 20.2% in the IBS3002 trial (P=0.001 for the 75-mg comparison
and P<0.001 for the 100-mg comparison) (Fig.1B).
The treatment effect of eluxadoline over placebo
was observed within the first week and was
maintained throughout the 26-week assessment
period (Fig.2, and Table S1 in the Supplementary Appendix).
Similar results were seen in the worst-case
analysis (Table2). In addition, both doses of
eluxadoline were significantly superior to placebo with respect to stool consistency, frequency,
and urgency, although no significant reduction
in episodes of incontinence was noted (Table2,
and Tables S2 and S3 in the Supplementary Appendix).
No significant improvement was seen in the
mean scores for the worst abdominal pain or in
the percentage of patients who reported an improvement of 30% or more in the score for the
worst abdominal pain (Table2). However, with
the use of more stringent measures of reduction
in these scores (i.e., 40% and 50%), significance was reached for eluxadoline at a dose of
100 mg in both study periods assessed (weeks
1 through 12 and weeks 1 through 26), as well
as for eluxadoline at a dose of 75 mg from weeks
1 through 12 (Table S2 in the Supplementary Appendix). At week 12, the symptoms of abdominal bloating were significantly less severe among
patients who received the 100-mg dose of eluxadoline than among those who received placebo
(Table S3 in the Supplementary Appendix).
Both doses of eluxadoline were significantly
superior to placebo with respect to the end points
of adequate relief of IBS symptoms, scores for
global symptoms, and scores on the IBS-QOL
questionnaire (Table2, and Table S3 in the Supplementary Appendix). Eluxadoline was significantly superior to placebo in all subpopulations
explored (Fig. S3 in the Supplementary Appendix).

Table 1. Demographic and Baseline Characteristics of the Patients.*

Characteristic
IBS-3001 Trial
IBS-3002 Trial
Placebo
(N=427)
Eluxadoline,
75 mg
(N=429)
Eluxadoline,
100 mg
(N=426)
Placebo
(N=382)
Eluxadoline,
75 mg
(N=381)
Eluxadoline,
100 mg
(N=383)
Age yr
45.814.1
44.513.2
44.413.9
47.113.8
45.013.2
45.713.3
Age 65 yr no. of patients (%)
51 (11.9)
29 (6.8)
35 (8.2)
51 (13.4)
36 (9.4)
39 (10.2)
Sex no. of patients (%)

Female
277 (64.9)
278 (64.8)
283 (66.4)
250 (65.4)
261 (68.5)
257 (67.1)
Male
150 (35.1)
151 (35.2)
143 (33.6)
132 (34.6)
120 (31.5)
126 (32.9)
Race no. of patients (%)

Black
46 (10.8)
46 (10.7)
48 (11.3)
43 (11.3)
46 (12.1)
51 (13.3)
White
370 (86.7)
374 (87.2)
368 (86.4)
329 (86.1)
327 (85.8)
318 (83.0)
Body-mass index
30.67.25
30.77.42
31.27.86
29.86.9
30.88.2
30.57.7
History of cholecystectomy
no. of patients (%)
89 (20.8)
85 (19.8)
98 (23.0)
69 (18.1)
81 (21.3)
74 (19.3)
Mean daily scores

Abdominal pain
6.21.6
6.11.5
6.21.5
6.01.5
6.01.5
6.01.5
Stool consistency
6.30.4
6.30.4
6.30.4
6.20.4
6.20.4
6.20.4
Abdominal bloating score
6.12.0
5.92.0
5.82.1
5.72.1
5.72.0
5.62.0
IBS-D global symptom score**
2.90.5
2.80.5
2.90.5
2.80.5
2.80.5
2.80.5
IBS-QOL questionnaire score
44.123.0
46.223.3
45.922.6
46.723.2
50.623.1
48.723.4
Episodes of urgency no.
3.72.7
3.52.2
3.52.1
3.42.0
3.42.2
3.64.1
Average daily bowel movements

no.
5.02.7
4.92.7
5.03.0
4.72.2
4.72.3
4.94.2
* Plusminus values are means SD. There were no significant differences between the three groups. IBS denotes irritable bowel syndrome,
and QOL quality of life.
Eluxadoline and placebo were administered twice a day.
Race was self-reported.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
The score for the worst abdominal pain and the abdominal bloating score were each recorded on a scale of 0 to 10, with 0 indicating no
symptoms and 10 the worst imaginable symptoms.
Stool consistency was assessed with the use of the Bristol Stool Form Scale, which ranges from 1 to 7, with 1 indicating hard stool and
7 indicating watery diarrhea.
** The IBS-D global symptom score was based on a scale of 0 to 4, with 0 indicating no symptoms and 4 very severe symptoms.
The IBS-QOL questionnaire consists of 34 items, each with a five-point response scale, with 1 indicating better quality of life and 5 worse
quality of life.
Frequency and urgency were recorded as the number of bowel movements and the number of episodes of urgency over the previous 24 hours.
Safety
Safety data were obtained from all patients up to

26 weeks (IBS-3002 trial) and through 52 weeks
(IBS-3001 trial). There were no treatment-related
trends in mean levels of serum chemical values
or hematologic values over time. Although isolated renal and metabolic events were reported,
there was no pattern across the study groups.
The most common adverse events were nausea, constipation, and abdominal pain (Table3).
Discontinuation of eluxadoline or placebo owing
to adverse events was infrequent. The rate of

discontinuation due to constipation was 1.1%
among patients who received eluxadoline at a
dose of 75 mg, 1.7% among patients who received eluxadoline at a dose of 100 mg, and
0.2% among patients who received placebo.
The rate of discontinuation due to nausea was
0.6% and 0% among patients who received 75-mg
and 100-mg doses of eluxadoline, respectively,
and 0.5% among patients who received placebo.
No deaths were reported during the study.

247
The
A Primary Efficacy End Point, Wk 112

100
Eluxadoline, 75 mg
Placebo
Eluxadoline, 100 mg
90
80
=8.0
Patients (%)
70
60
=13.4
=6.8
=12.7
50
23.9 25.1
30
17.1
20
=9.5
**
**
28.9 29.6
40
=10.3
**
**
26.2 27.0
16.2
16.7
10
IBS-3001 Trial
IBS-3002 Trial
09
06
N
=8
08
=8
N
=8
82
82
N
=3
81
=3
N
=3
27
26
=4
N
=4
N
=4
27
Pooled Data
B Primary Efficacy End Point, Wk 126

100
Eluxadoline, 75 mg
Placebo
Eluxadoline, 100 mg
90
80
=10.3
Patients (%)
70
60
=12.5
=4.4
=10.2
50
19.0
=7.2
**
*
30.4 32.7
**
29.3
40
30
=11.5
23.4
**
**
31.0
26.7
20.2
19.5
20
10
IBS-3001 Trial
IBS-3002 Trial
09
06
=8
N
=8
N
08
=8
N
82
82
N
=3
N
=3
81
=3
N
27
26
=4
N
=4
N
=4
27
Pooled Data
Figure 1. Primary Efficacy End Point in the Eluxadoline and Placebo Groups
in Each Trial and in the Pooled Trials.
The primary efficacy end point was defined as the proportion of patients
who recorded a reduction of 30% or more from baseline in the daily average score for their worst abdominal pain for at least 50% of days assessed
and, on the same days, a daily stool-consistency score of less than 5 (on a
scale of 1 to 7, with 1 indicating hard stool and 7 indicating watery diarrhea),
for weeks 1 through 12 (Panel A) and for weeks 1 through 26 (Panel B).
The single asterisk denotes P<0.05 vs. placebo, and the double asterisk
P<0.001 vs. placebo.
Asingle case of self-limited ischemic colitis

occurred in a 72-year-old woman who received
100 mg of eluxadoline; she had a history of cirrhosis and was receiving aspirin. Serious adverse
events occurred in 4.2% of the patients who received eluxadoline at a dose of 75 mg, 4.8% of
the patients who received eluxadoline at a dose
of 100 mg, and 3.0% of the patients who received
placebo. Two patients in the 100-mg eluxadoline
248
of
m e dic i n e
group had respiratory failure; one had numerous

predisposing risk factors, whereas the other had
an exacerbation of asthma that resulted in a
stress cardiomyopathy (Table S4 in the Supplementary Appendix).
Five patients (two in the 75-mg eluxadoline
group and three in the 100-mg eluxadoline group)
had serious adverse events that were determined
by the adjudication committee to be pancreatitis.
Eight patients (one who received eluxadoline at a
dose of 75 mg and seven who received eluxadoline at a dose of 100 mg) had acute abdominal
pain associated with abrupt increases in liverenzyme levels; in one of the eight patients, this
adverse event was serious. One of the five cases
of pancreatitis (in the 100-mg group) and all eight
cases of abdominal pain with elevation of hepatic enzyme levels were determined by the adjudication committee to be consistent with spasm
of the sphincter of Oddi. This determination was
made after the committees positive response to
the question Is the event consistent with an
acute reversible pancreatic or biliary duct obstruction? All nine of these cases were associated
with the absence of a gallbladder, and seven occurred within 2 weeks after the initiation of treatment. Of the remaining four events of pancreatitis, one was associated with biliary sludge and
three were associated with excessive alcohol consumption (additional information was collected
retrospectively).
Adverse reactions of euphoria were not reported among any patients who received eluxadoline
at a dose of 75 mg; these reactions were reported
in 0.2% of the patients (2 of 859 patients) who
received eluxadoline at a dose of 100 mg. Adverse reactions of feeling drunk were reported in
0.1% of the patients who received 75 mg of eluxadoline (1 of 807 patients) and in 0.1% of patients who received 100 mg of eluxadoline (1 of
859 patients). Neither of these reactions were
reported in the placebo group.
Neither symptoms recorded daily during the
single-blind placebo withdrawal period nor the
adverse-event profile during the follow-up periods
suggested any worsening of symptoms of IBS with
diarrhea or symptoms of withdrawal after the
end of treatment (Tables S5 and S6, and Fig. S4
in the Supplementary Appendix). Median scores
on the Subjective Opiate Withdrawal Scale, on
which scores range from 0 to 64, with higher
scores indicating more intense symptoms of

100
Placebo
Eluxadoline 75 mg
90
Eluxadoline 100 mg
80
Patients (%)
70
60
50
40
30
20
10
0
14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 147 154 161 168 175 182
Days
Figure 2. Percentage of Patients Who Met the Daily Composite Response Criteria over Time.
Data are pooled from the two phase 3 studies.
withdrawal, were nearly identical in the eluxadoline and placebo groups. The median scores were
2 (range, 0 to 54) among the patients who received eluxadoline at a dose of 75 mg, 3 (range,
0 to 56) among the patients who received eluxadoline at a dose of 100 mg, and 3 (range, 0 to
56) among the patients who received placebo.
Discussion
In these studies involving patients with IBS and
diarrhea, eluxadoline was effective in simultaneously relieving the symptoms of abdominal pain
and diarrhea. Our primary outcome measure
required simultaneous improvement in the daily
scores for the worst abdominal pain and stool
consistency on the same day for at least 50% of
the days assessed; this end point is currently one
of those recommended by the regulatory agencies in the United States and Europe to show
treatment effect in trials involving patients with
IBS and diarrhea. More patients who received
eluxadoline than who received placebo reported
significant improvement in the primary outcome
measure over both intervals assessed (absolute
differences for the two doses across the two
studies ranged from 7 to 13 percentage points
for weeks 1 through 12, and from 4 to 13 percentage points for weeks 1 through 26; the difference for the 75-mg dosage was not statisti-
cally significant for weeks 1 through 26 in one

study).
Patients who received eluxadoline reported a
decrease in stool frequency and in urgency,
which are two of the most bothersome symptoms of IBS with diarrhea. Eluxadoline was also
significantly superior to placebo with respect to
global assessments (on measures of adequate
relief of IBS symptoms, global symptoms, and
quality of life), particularly at the 100-mg twicedaily dose, with treatment effects on adequate
relief of IBS symptoms that were similar to those
reported with alosetron and rifaximin.5,18 The
use of eluxadoline did not result in significantly
higher rates of the prespecified secondary outcome of 30% improvement in the average score
for the worst abdominal pain than the rates with
placebo. Significant differences were seen when
higher thresholds of improvement in this score
(i.e., 40% and 50%) were assessed (Table S2 in
the Supplementary Appendix). Studies of loperamide have shown a decrease in diarrhea but
minimal effect on abdominal pain.19-21
The most common adverse events in the
patients who received eluxadoline at a dose of
100 mg were constipation (in 8.6% of the patients) and nausea (in 7.5%). Rates of discontinuation due to adverse events were infrequent
(among 1.1%, 1.7%, and 0.2% of patients because of constipation and among 0.6%, 0%, and

249
250
Eluxadoline,
75 mg
(N=427)
226 (52.9)
0.008
0.05
0.008
0.40
0.01
P Value
231 (54.2)
148 (34.7)
146 (34.3)
184 (43.2)
103 (24.2)
no. of patients
with response (%)
Eluxadoline,
100 mg
(N=426)
0.002
0.06
<0.001
0.28
0.006
P Value
Eluxadoline,
75 mg
(N=381)
188 (49.2)
113 (29.6)
80 (20.9)
173 (45.3)
53 (13.9)
229 (60.1)
166 (43.6)
141 (37.0)
183 (48.0)
108 (28.3)
no. of patients
with response (%)
Placebo
(N=382)
0.003
<0.001
<0.001
0.45
<0.001
P Value
IBS-3002 Trial*
223 (58.4)
162 (42.4)
136 (35.6)
195 (51.0)
108 (28.3)
no. of patients
with response (%)
Eluxadoline,
100 mg
(N=382)
0.01
<0.001
<0.001
0.11
<0.001
P Value
* Eluxadoline and placebo were administered twice a day.

A patient who had a response was defined as a patient who met the daily pain response criterion (worst abdominal pain score in the past 24 hours improved by 30%, as compared
with baseline pain) on 50% of days or more on which this outcome was recorded in an electronic diary during the interval and who had a minimum of 60 days of diary data from weeks
1 through 12.
A patient who had a response was defined as a patient who met the daily stool consistency response criterion (Bristol Stool Form Scale score <5, or a diary entry reporting the absence
of a bowel movement if accompanied by a 30% improvement in worst abdominal pain score as compared with baseline) on 50% of days or more on which this outcome was recorded
in an electronic diary during the interval and who had a minimum of 60 days of diary data from weeks 1 through 12.
The IBS-D global symptom score is based on a scale of 0 to 4, with 0 indicating no symptoms and 4 very severe symptoms. A patient who had a response was defined as a patient who
met the daily IBS-diarrhea global symptom score criterion (a global symptom score of 0 or 1, or a daily score improved by 2.0 as compared with the baseline average) on 50% of days
or more during the interval and who had a minimum of 60 days of diary data from weeks 1 through 12.
A patient who met this end point had a weekly response of yes when asked whether he or she had adequate relief of symptoms of IBS with diarrhea for 50% or more of the total
weeks during the interval and had a minimum of 6 weeks of data for the 12-week interval.
187 (43.8)
Adequate relief of IBS

symptoms
150 (35.1)
128 (30.0)
94 (22.0)
123 (28.8)
Stool consistency
IBS-D global symptoms
100 (23.4)
181 (42.4)
71 (16.6)
169 (39.6)
Worst-case analysis
no. of patients
with response (%)
Placebo
(N=427)
IBS-3001 Trial*
Abdominal pain
End Point
Table 2. Secondary Efficacy End Points (Weeks 112).
The
of
m e dic i n e

Table 3. Common Adverse Events.*

Placebo
(N=808)
Event
Eluxadoline
75 mg
(N=807)
100 mg
(N=859)
Combined
Groups
(N=1666)
no. of patients (%)

Adverse events
All adverse events
450 (55.7)
486 (60.2)
500 (58.2)
986 (59.2)
24 (3.0)
34 (4.2)
41 (4.8)
75 (4.5)
8 (1.0)
12 (1.5)
17 (2.0)
29 (1.7)
Pancreatitis
2 (0.2)
3 (0.3)
5 (0.3)
Spasm of the sphincter of Oddi
1 (0.1)
7 (0.8)
8 (0.5)
20 (2.5)
60 (7.4)
74 (8.6)
134 (8.0)
Nausea
41 (5.1)
65 (8.1)
64 (7.5)
129 (7.7)
Abdominal pain
33 (4.1)
47 (5.8)
62 (7.2)
109 (6.5)
Vomiting
11 (1.4)
32 (4.0)
36 (4.2)
68 (4.1)
Abdominal distention
13 (1.6)
21 (2.6)
22 (2.6)
43 (2.6)
Gastroenteritis
27 (3.3)
36 (4.5)
19 (2.2)
55 (3.3)
Flatulence
13 (1.6)
21 (2.6)
27 (3.1)
48 (2.9)
Upper respiratory tract infection
32 (4.0)
27 (3.3)
47 (5.5)
74 (4.4)
Bronchitis
18 (2.2)
26 (3.2)
27 (3.1)
53 (3.2)
Sinusitis
26 (3.2)
27 (3.3)
24 (2.8)
51 (3.1)
Nasopharyngitis
27 (3.3)
33 (4.1)
23 (2.7)
56 (3.4)
Dizziness
17 (2.1)
21 (2.6)
28 (3.3)
49 (2.9)
Anxiety
14 (1.7)
10 (1.2)
19 (2.2)
29 (1.7)
Increased level of alanine aminotransferase
12 (1.5)
17 (2.1)
26 (3.0)**
43 (2.6)
Serious adverse events

Cardiac events
Most common adverse events

Constipation
* Values are pooled data from the IBS-3001 trial (52 weeks of double-blind safety data) and the IBS-3002 trial (26 weeks
of double-blind safety data). The respective durations (person-years) of exposure were as follows: placebo group,
433.6 person-years; 75-mg eluxadoline group, 417.4 person-years; 100-mg eluxadoline group, 429.5 person-years; and
the combined eluxadoline groups, 846.9 person-years.
Eluxadoline and placebo were administered twice a day for 52 weeks in the IBS-3001 trial and for 26 weeks in the IBS3002 trial.
The most common adverse events listed were reported in 2.0% or more of the patients in any of the study groups.
All constipation events were nonserious. A total of 1.4% of patients who received eluxadoline and 0.2% who received
placebo discontinued their use because of nonserious constipation.
The term abdominal pain includes the conditions coded as abdominal pain, upper abdominal pain, and lower abdominal pain.
The term gastroenteritis includes the conditions coded as gastroenteritis and viral gastroenteritis.
** Seven of the 26 cases of increased levels of alanine aminotransferase occurred in patients who were determined by
the adjudication committee to have spasm of the sphincter of Oddi.
0.5% of patients because of nausea in the 75-mg

eluxadoline, 100-mg eluxadoline, and placebo
groups, respectively). In trials of alosetron, the
rates of discontinuation due to adverse events
were 10 to 15% among patients who received
alosetron and 7 to 9% among patients who received placebo.22,23
Five cases of pancreatitis (0.3%) and 8 cases

of abdominal pain with elevated levels of hepatic
enzymes (0.5%) occurred in this study. Nine of
these 13 cases were determined by the adjudication committee to be associated with spasm of
the sphincter of Oddi. All cases of pancreatitis
did not involve organ failure or local or systemic

251
The
complications, occurred in patients with either

biliary disorders (spasm of the sphincter of Oddi
and biliary sludge) or alcohol use (3 of 5 cases),
and resolved within the first week after the onset of pancreatitis.24 The presence of only mild
cases does not preclude the risk of severe cases
in the future, nor do these associations preclude
other at-risk populations. Data are lacking from
studies to assess whether the risk of pancreatitis
can be reduced if treatment is restricted to patients with gallbladders or to those who abstain
from excessive alcohol use. Identifying patients
with IBS with diarrhea who are at risk for acute
pancreatitis because of the absence of a gallbladder or excessive alcohol consumption is important before initiating therapy with eluxadoline. Any benefit will need to be considered in
the context of side effects and risks.
Alcohol has been shown to alter pancreatic
ductal and periductal anatomy,25-27 as well as to
contribute to increases in pressure at the sphincter of Oddi,28,29 which may have exacerbated the
known association of pancreatitis30-35 and spasm
of the sphincter of Oddi with -opioid receptor
agonists.36-43 Spasm of the sphincter of Oddi occurred exclusively in patients who did not have a
gallbladder; there were no cases of spasm of the
sphincter of Oddi among the 1318 patients with
a gallbladder who received eluxadoline.
References
1. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges
and hope for the future. J Manag Care
Pharm 2004;10:299-309.
2. Par P, Gray J, Lam S, et al. Healthrelated quality of life, work productivity,
and health care resource utilization of
subjects with irritable bowel syndrome:
baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal
Symptoms in Canada), a naturalistic study.
Clin Ther 2006;28:1726-35.
3. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the
United States: 2012 update. Gastroenterology 2012;143:1179-87.
4. Ford AC, Moayyedi P, Lacy BE, et al.
American College of Gastroenterology
monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol
2014;109:Suppl 1:S2-S26.
5. Pimentel M, Lembo A, Chey WD, et al.
Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22-32.
6. Andresen V, Montori VM, Keller J,
252
of
m e dic i n e
In summary, in two phase 3 trials involving

women and men with IBS with diarrhea, treatment with eluxadoline, a poorly absorbed,12
peripherally active, mixed - and -opioid receptor agonist and -opioid receptor antagonist,
resulted in a decrease in symptoms of IBS with
diarrhea. Pancreatitis developed in 5 of 1666 patients (0.3%), and abdominal pain with elevated
hepatic-enzyme levels developed in 8 of 1666
patients (0.5%). Future studies should be aimed
at identifying subpopulations of patients with
IBS with diarrhea who may best benefit from
eluxadoline.
Supported by Furiex Pharmaceuticals, an affiliate of Allergan.
Dr. Lembo reports receiving fees for serving on advisory
boards from Allergen, Furiex Pharmaceuticals, Prometheus
Laboratories, Salix Pharmaceuticals, Valeant Pharmaceuticals,
Forest Laboratories, Alkermes, AstraZeneca, and Ironwood
Pharmaceuticals. Dr. Lacy reports receiving fees for serving on
advisory boards from Ironwood Pharmaceuticals, Forest Laboratories, Prometheus Laboratories, and Salix Pharmaceuticals.
Drs. Dove, Andrae, Davenport, McIntyre, Lopez, and Covington
and Ms. Turner report being employees of Activis (formerly
Furiex Pharmaceuticals), and Drs. Dove, Andrae, McIntyre, Lopez,
and Covington and Ms. Turner, holding stock in Furiex Pharmaceuticals. No other potential conflict of interest relevant to this
article was reported. Disclosure forms provided by the authors
are available with the full text of this article at NEJM.org.
We thank David McMinn, Ph.D., of Complete HealthVizion for
editorial assistance with an earlier version of the manuscript,
Fred Eshelman, Pharm.D., (former chairman of the board,
Furiex Pharmaceuticals) for his support of this project, and June
Almenoff, M.D., Ph.D., (former president, Furiex Pharmaceuticals) for contributions to the conduct of the project.
West CP, Layer P, Camilleri M. Effects of

5-hydroxytryptamine (serotonin) type 3
antagonists on symptom relief and constipation in nonconstipated irritable bowel
syndrome: a systematic review and metaanalysis of randomized controlled trials.
Clin Gastroenterol Hepatol 2008;6:545-55.
7. Chang L, Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA. A doseranging, phase II study of the efficacy and
safety of alosetron in men with diarrheapredominant IBS. Am J Gastroenterol
2005;100:115-23.
8. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155:
11-7.
9. Bauer AJ, Sarr MG, Szurszewski JH.
Opioids inhibit neuromuscular transmission in circular muscle of human and
baboon jejunum. Gastroenterology 1991;
101:970-6.
10. Ananthan S. Opioid ligands with
mixed mu/delta opioid receptor inter
actions: an emerging approach to novel
analgesics. AAPS J 2006;8(1):E118-E125.
11. Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG.
S imultaneous targeting of multiple opioid

receptors: a strategy to improve side-effect
profile. Br J Anaesth 2009;103:38-49.
12. Wade PR, Palmer JM, McKenney S,
et al. Modulation of gastrointestinal function by MuDelta, a mixed opioid receptor agonist/ opioid receptor antagonist.
Br J Pharmacol 2012;167:1111-25.
13. Dove LS, Lembo A, Randall CW, et al.
Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a
phase 2 study. Gastroenterology 2013;145:
329-38.
14. Longstreth GF, Thompson WG, Chey
WD, et al. Functional bowel disorders.
Gastroenterology 2016;130:1480-91.
15. American Psychiatric Association.
Diagnostic and statistical manual of mental disorders, fourth edition, text revision:
DSM-IV-TR. Washington, DC:American
Psychiatric Press, 2000.
16. Department of Health and Human
Services, National Institutes of Health.
NIAAA newsletter. Winter 2004 (http://
www.niaaa.nih.gov/sites/default/f iles/
newsletters/Newsletter_Number3.pdf).
17. Handelsman L, Cochrane KJ, Aronson

MJ, Ness R, Rubinstein KJ, Kanof PD. Two

new rating scales for opiate withdrawal.
Am J Drug Alcohol Abuse 1987;13:293308.
18. Camilleri M, Chey WY, Mayer EA, et al.
A randomized controlled clinical trial of
the serotonin type 3 receptor antagonist
alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch
Intern Med 2001;161:1733-40.
19. Cann PA, Read NW, Holdsworth CD,
Barends D. Role of loperamide and placebo
in management of irritable bowel syndrome (IBS). Dig Dis Sci 1984;29:239-47.
20. Efskind PS, Bernklev T, Vatn MH.
A double-blind placebo-controlled trial
with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996;
31:
463-8.
21. Lav B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel
syndrome a double-blind placebo controlled study. Scand J Gastroenterol Suppl
1987;130:77-80.
22. Lembo AJ, Olden KW, Ameen VZ,
Gordon SL, Heath AT, Carter EG. Effect of
alosetron on bowel urgency and global
symptoms in women with severe, diarrheapredominant irritable bowel syndrome:
analysis of two controlled trials. Clin
Gastroenterol Hepatol 2004;2:675-82.
23. Lembo T, Wright RA, Bagby B, et al.
Alosetron controls bowel urgency and
provides global symptom improvement in
women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol
2001;96:2662-70.
24. Banks PA, Bollen TL, Dervenis C, et al.
Classification of acute pancreatitis
2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102-11.
25. Kagaya T, Takebe T, Koizumi M, Kata-
oka S, Kamei T, Oyama K. Effect of long

term alcohol feeding on the pancreas in
rat. Gastroenterol Jpn 1979;14:327-35.
26. Pandol SJ, Raraty M. Pathobiology of
alcoholic pancreatitis. Pancreatology 2007;
7:105-14.
27. Shahedi K, Pandol SJ, Hu R. Oxidative
stress and alcoholic pancreatitis. J Gastroenterol Hepatol Res 2013;2:335-42.
28. Guelrud M, Mendoza S, Rossiter G,
Gelrud D, Rossiter A, Souney PF. Effect of
local instillation of alcohol on sphincter
of Oddi motor activity: combined ERCP
and manometry study. Gastrointest Endosc 1991;37:428-32.
29. Viceconte G. Effects of ethanol on the
sphincter of Oddi: an endoscopic manometric study. Gut 1983;24:20-7.
30. Badalov N, Baradarian R, Iswara K,
Li J, Steinberg W, Tenner S. Drug-induced
acute pancreatitis: an evidence-based review. Clin Gastroenterol Hepatol 2007;5:
648-61.
31. Hastier P, Longo F, Buckley M, Chichmanian RM, Delmont JP. Pancreatitis induced by codeine: a case report with positive rechallenge. Gut 1997;41:705-6.
32. Hastier P, Buckley MJ, Peten EP, et al.
A new source of drug-induced acute pancreatitis: codeine. Am J Gastroenterol
2000;95:3295-8.
33. Howaizi M, Sba-Idrissi MS, Baillet P.
Loperamide-induced acute pancreatitis.
Gastroenterol Clin Biol 2000;
24:
589-91.
(In French.)
34. Trivedi CD, Pitchumoni CS. Drug-
induced pancreatitis: an update. J Clin
Gastroenterol 2005;39:709-16.
35. Vidarsdottir H, Vidarsdottir H, Moller
PH, Bjornsson ES. Loperamide-induced
acute pancreatitis. Case Rep Gastrointest
Med 2013:517414.
36. Behar J, Biancani P. Neural control of
the sphincter of Oddi: physiologic role of

enkephalins on the regulation of basal
sphincter of Oddi motor activity in the
cat. Gastroenterology 1984;86:134-41.
37. Helm JF, Venu RP, Geenen JE, et al.
Effects of morphine on the human sphincter of Oddi. Gut 1988;29:1402-7.
38. Mossberg SM, Bloom A, Berkowitz J,
Ross G. Serum enzyme activities following morphine: a study of transaminase
and alkaline phosphatase levels in normal
persons and those with gallbladder disease. Arch Intern Med 1962;109:429-37.
39. Patch GG, Morton KA, Arias JM, Datz
FL. Naloxone reverses pattern of obstruction of the distal common bile duct induced by analgesic narcotics in hepatobiliary imaging. J Nucl Med 1991;32:1270-2.
40. Roberts-Thomson IC, Pannall PR,
Toouli J. Relationship between morphine
responses and sphincter of Oddi motility
in undefined biliary pain after cholecystectomy. J Gastroenterol Hepatol 1989;4:
317-24.
41. Steinberg WM, Salvato RF, Toskes PP.
The morphine-prostigmin provocative test
is it useful for making clinical decisions? Gastroenterology 1980;78:728-31.
42. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of
the data and therapeutic implications in
treating pancreatitis. Am J Gastroenterol
2001;96:1266-72.
43. Thune A, Jivegrd L, Pollard H,
Moreau J, Schwartz JC, Svanvik J. Location of enkephalinase and functional effects of [Leu5]enkephalin and inhibition
of enkephalinase in the feline main pancreatic and bile duct sphincters. Clin Sci
(Lond) 1992;82:169-73.
Copyright 2016 Massachusetts Medical Society.
nejm clinical practice center
Explore a new page designed specifically for practicing clinicians,

the NEJM Clinical Practice Center, at NEJM.org/clinical-practice-center.
Find practice-changing research, reviews from our Clinical Practice series,
a curated collection of clinical cases, and interactive features
designed to hone your diagnostic skills.

253

Nej Mo A 1505180

Uploaded by

Copyright:

Available Formats

Nej Mo A 1505180

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nej Mo A 1505180

Uploaded by

Copyright:

Available Formats

The

Eluxadoline for Irritable Bowel Syndrome

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

Eluxadoline for Irritable Bowel Syndrome

he irritable bowel syndrome (IBS)

We enrolled patients who were 18 to 80 years of

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

abuse15 or binge drinking,16 pancreatitis, sphincter

We conducted two randomized, double-blind,

and collected patient-reported daily symptoms of

The trials were designed by the first author and

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

Eluxadoline for Irritable Bowel Syndrome

withdrawal. This scale includes 16 symptoms of

The New England Journal of Medicine

Efficacy analyses of pooled data from the two

A total of 2428 patients (1282 in the IBS-3001

From weeks 1 through 12, the proportion of

placebo) and in the IBS-3002 trial (28.9% and

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

Eluxadoline for Irritable Bowel Syndrome

Table 1. Demographic and Baseline Characteristics of the Patients.*

Age 65 yr no. of patients (%)

Sex no. of patients (%)

Race no. of patients (%)

Mean daily scores

Abdominal bloating score

IBS-D global symptom score**

IBS-QOL questionnaire score

Episodes of urgency no.

Average daily bowel movements

Safety data were obtained from all patients up to

to adverse events was infrequent. The rate of

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

A Primary Efficacy End Point, Wk 112

B Primary Efficacy End Point, Wk 126

Asingle case of self-limited ischemic colitis

group had respiratory failure; one had numerous

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

Eluxadoline for Irritable Bowel Syndrome

cally significant for weeks 1 through 26 in one

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

* Eluxadoline and placebo were administered twice a day.

Adequate relief of IBS

IBS-D global symptoms

Table 2. Secondary Efficacy End Points (Weeks 112).

n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

Eluxadoline for Irritable Bowel Syndrome

Table 3. Common Adverse Events.*

no. of patients (%)

Spasm of the sphincter of Oddi

* Eluxadoline and placebo were administered twice a day.