Journal Pone 0302302
Journal Pone 0302302
Journal Pone 0302302
STUDY PROTOCOL
OPEN ACCESS
data availability statement will be made available and questionnaires at 2 months about their beliefs and intention to consult for similar future
after study completion. illnesses. Primary care medical records are also reviewed at 6-months to collect further
Funding: The trial was funded by the NIHR Efficacy infection consultations, antibiotic prescribing and hospital admissions. The trial aims to
and Mechanism Evaluation Programme recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute
(NIHR131758) that was awarded to Prof Alastair D
Hay. LY is also funded by NIHR as a Senior
reduction in antibiotic prescribing.
Investigator and some of her time on this project Qualitative interviews are being conducted with approximately 20 clinicians and 30 partic-
may have been supported by the funding she ipants to understand any changes in beliefs and behaviour resulting from the point-of-care-
received from the NIHR Applied Research
test and generate attributes for clinician and patient discrete choice experiments.
Collaboration West and NIHR Health Protection
Research Unit.
Discussion
Competing interests: The authors have declared
that no competing interests exist. This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid
Abbreviations: AE, Adverse Event; AMR, microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary
Antimicrobial resistance; DCE, Discrete Choice care.
Experiment; GP, General practitioner; MCID,
Minimally clinically important difference; PCMR,
Primary care medical record; POCT, Point-of-care-
Trial registration
test; PPI, Patient and public involvement; RCT, ISRCTN16039192, prospectively registered on 08/11/2022.
Randomised Controlled Trial; RSV, Respiratory
Syncytial virus; RTI, Respiratory Tract Infection;
SAE, Serious Adverse Event; SUSAR, Suspected
Unexpected Serious Adverse Reaction; VTM, Viral
Transport Medium.
Introduction
Respiratory tract infections (RTIs) are the most common problem managed by health services
worldwide [1]. In the UK, antibiotics are prescribed for over 50% of RTIs by general practi-
tioners (GP) and primary care nurses [2, 3], with 50% of these prescriptions considered inap-
propriate [4, 5], and despite strong evidence that the majority of patients do not benefit [6–9].
The overprescribing of antibiotics results in unnecessary side effects [10], depletion of normal
flora [11], increased healthcare costs [12], and fuels antimicrobial resistance (AMR) [13, 14],
which is regarded as a significant public health threat [15]. High antibiotic treatment rates are
attributed to clinician uncertainty regarding patients’ microbiological diagnosis and clinical
prognosis [16, 17], leading to ‘just-in-case’ defensive prescribing [17].
One potential solution to address this issue is point-of care-testing (POCT) in primary care
settings. Rapid microbiological POCTs (POCTRMs) use nucleic acid or antigen-based tests to
detect viruses and bacteria from respiratory tract samples in as little as 15 minutes [18]. While
multiplex POCTRMs have shown promising results in reducing hospital admission times and
length of antibiotic courses in secondary care [19–22], more research is needed to evaluate
their impact on antibiotic use and clinical outcomes in primary care.
Observational studies [23, 24] have reported on the effects of POCTRMs testing for Influenza
A and B, and/or respiratory syncytial virus (RSV) in primary care. However, none of these
studies evaluated the use of multiplex POCTRMs on antibiotic prescribing or clinical outcomes.
We conducted a mixed-methods, observational feasibility study [25] which suggested a multi-
plex POCTRM was acceptable in primary care, and helped improve diagnostic certainty. How-
ever, none of these studies used randomised controlled trial methods, and none assessed the
short- and long-term effects of POCTRM testing on clinician and patient beliefs and behaviour.
To address this evidence gap, the RAPID-TEST study will conduct a RCT with the aim of
comparing decision making, antibiotic prescribing and patient outcomes between individuals
allocated to a POCT group and those allocated to a usual care group, at approximately 16 pri-
mary care practices in the south west of England.
Population
The trial is aiming to recruit 514 patients aged �12 months presenting to primary care with a
suspected RTI where the Study Clinician and/or patient believes antibiotic treatment is, or
may be, necessary. Patients can present to their GP practice face-to-face, via telephone or via
online appointment. Study Clinicians can be any member of staff at the practice that is usually
responsible for the care of patients with RTIs (GPs, nurses, paramedics and pharmacists) and
who have been trained in study procedures.
Patients must meet all the following criteria to be eligible to take part:
1. Aged �12 months on the day of presentation
2. Presenting to primary care for the first time in this episode, and within 21 days of illness
onset, with a Study Clinician suspected acute RTI. Symptoms may include one or more of:
a. Sore throat
b. Runny nose
c. Earache
d. Cough
e. Sputum
f. Wheeze
g. Shortness of breath
3. Study Clinician diagnoses of an upper or lower RTI such as:
j. Infective exacerbation of chronic lung disease e.g. asthma, chronic obstructive pulmonary
disease (COPD), emphysema or bronchiectasis
4. Study Clinician or patient/parent/carer believes antibiotic treatment is, or may be,
necessary
5. Patient/parent/carer willing and able to give informed consent
6. Patient/parent/carer willing for patient to have a nasal and throat swab taken, or willing
and able to collect, self-take and promptly return the swab to the site
7. Study Clinician and patient/parent/carer willing to wait for the POCTRM result before an
antibiotic prescribing decision is made
8. Laboratory transport pick up for samples expected <24 hours e.g. sample is expected to be
ready prior to final sample collection on a Friday
9. Patient/parent/carer willing to complete Trial Diary and for outcome data to be collected
from medical record
Patients with any of the following criteria are excluded:
1. Known to have cystic fibrosis
2. Require hospital admission
3. Previously taken part in the RAPID-TEST RCT
4. Currently taking part in another conflicting RTI study.
Patients already being treated with antibiotics or antivirals (for any indication) are
eligible as long as the Study Clinician suspects a new (or ongoing) RTI, and the Study Cli-
nician and/or patient/ parent/ carer believe further antibiotic treatment is, or may be,
necessary.
Co-enrolment to other research studies are considered on a case-by-case basis.
Objectives
Clinical objectives. The primary clinical objective is to investigate whether the use of a
rapid POCTRM can reduce same-day antibiotic prescribing for children and adults presenting
to primary care with RTIs where the Study Clinician and/or patient believes antibiotic treat-
ment is, or may be, necessary.
The key secondary clinical objective is to investigate whether the use of a rapid POCTRM
changes participant reported symptom severity on days 2 to 4.
Other clinical secondary objectives include:
a) To investigate whether the use of a rapid POCTRM changes participant reported severity
and duration of symptoms over 28 days including any hospital admissions for respiratory
symptoms, antibiotic consumption, and time to return to normal activities.
b) To investigate whether the use of a rapid POCTRM changes participant (or parent/carer if
the participant is <16 years) confidence in the clinical management of the infection, and
their intention to consult for future similar illnesses
c) To investigate whether the use of a rapid POCTRM changes subsequent healthcare resource
use in the following six months
Qualitative objectives.
d) To explore participants’ (or parents’/carers’ if the participant is <16 years) understanding
of the test and the result they were given, and their views of the implications for treatment
and future consultations
e) To explore the trade-offs participants (or parents/carers if the participant is <16 years)
make in choosing to visit the GP with respiratory infection symptoms and the extent
POCTRMs might increase or decrease help seeking behaviour
f) To describe the situations in which clinicians most and least value the new microbial knowl-
edge, and how it may influence clinical reasoning and participant management
g) To explore the trade-offs clinicians make about whether and when to use the POCTRM
Mechanistic objectives
h) To determine whether there are overall (intervention vs. control) and differential (virus
detected vs. not detected) effects with respect to reducing the number of participants for
whom the Study Clinician believes antibiotics are necessary
i) To describe the effect of POCTRM results on Study Clinician and participant (or parent/
carer if the participant is <16 years) beliefs in the necessity, and benefits, of prescribing
antibiotics for the respiratory infection, and confidence in the value of the POCTRM to
guide the prescribing decision and explore relationships of Study Clinician and participant
(or parent/carer if the participant is <16 years) beliefs, attitudes and intentions with antibi-
otic prescribing and consumption.
necessary. Swabs are placed in a tube with viral transport medium (VTM) before being tested
at the practice, if randomised to the intervention, and sent to the central laboratory.
Randomisation
Once a swab has been provided, participants are individually randomised 1:1 to intervention
(GP POCTRM test) or control (No GP POCTRM test) using an internet-based randomisation
system developed and maintained by Sealed Envelope™ to ensure concealment. Randomisation
is stratified by age (<16 years vs. �16 years) and chronic lung disease, defined as asthma,
chronic obstructive pulmonary disease (COPD), emphysema or bronchiectasis (present vs.
absent). It is not possible to blind allocation since subsequent trial processes differ by group.
Immediately following randomisation, the Study Clinician is informed of the allocation so that
clinical management of control group patients can proceed (management of intervention
group participants should wait for POCTRM results).
Intervention
A portion of the VTM from the swab sample from participants in the GP POCTRM test group
is analysed as soon as possible using the BioFire1 FilmArray1 Torch 1 in conjunction with
BioFire1 RP2.1 plus reagent pouches (Biomerieux) according to the manufacturer’s instruc-
tions at the GP practice. The time for processing one swab to results being available is approxi-
mately 1 hour, assuming the Torch 1 machine is not already in use. The results indicate
presence or absence of 23 upper respiratory microbes: 19 viruses (Influenza A (no subtype
detected, H1, H1-2009, H3), Influenza B, Adenovirus, Coronaviruses (HKU1, NL63, 229E,
OC43, Mers-CoV, SARS-CoV-2), Human Metapneumovirus, Human Rhinovirus/ Enterovi-
rus (not possible to distinguish due to genetic similarity), Parainfluenza (types 1, 2, 3, 4) and
RSV and four atypical bacteria: Bordetella pertussis, Bordetella parapertussis, Chlamydia pneu-
moniae and Mycoplasma pneumonia.
Study Clinicians are advised during trial set up and training that the POCTRM result should
be used as a guide to clinical decision making, with final responsibility for antibiotic prescrib-
ing residing with the Study Clinician. To help with results interpretation, Study Clinicians are
provided with information describing the typical presentation of illnesses caused by the
microbes tested (S1 Appendix).
If the POCTRM results are reported as ‘failed’, ‘invalid’ or ‘equivocal’, the original swab sam-
ple is retested as per the manufacturer’s instructions. If it is not possible to obtain POCTRM
results after following the manufacturer’s instructions the participant continues in the trial
and the Study Clinician makes an antibiotic prescribing decision based on the clinical evidence
available at that time.
‘Appointment two’
Appointment two takes place on the same day as randomisation.
For participants randomised to the GP POCTRM group, the Study Clinician waits to receive
the POCTRM test results, and then completes a second set of ‘Study Clinician Views’ (Table 1)
and then contacts the participant to inform them of the randomisation outcome and discuss
treatment.
If the participant has been randomised to the No GP POCTRM group, the Study Clinician
can proceed to complete their second set of ‘Study Clinician Views’, contact the participant,
inform them of the randomisation outcome and discuss treatment.
Filmarray1 Torch 1 system used at the GP practices. At the end of the study any residual sam-
ple will be destroyed. All samples are handled according to the Human Tissue Act.
Follow up
All participants (or parent/carer if the participant is <16 years) are asked to complete a vali-
dated Trial Diary [27] until symptoms resolve (defined as all symptoms being rated zero for
two consecutive days) or up to day 28, whichever comes first. The central trial team contacts
participants via email, text or phone to support completion of the Trial Diary.
Participants (or parent/carer if the participant is <16 years) are sent a follow-up question-
naire at 2 months to collect beliefs and intention to consult for similar future illnesses (see S1
Appendix). Up to two reminders are sent where questionnaires are not returned.
In addition to Trial Diaries and questionnaires, data on any further GP consultations for
RTIs are collected from participants’ primary care medical records (PCMR) at 2 and 6 months
by site staff.
Outcome measures
The primary clinical efficacy outcome is antibiotic prescribing for a RTI at Appointment Two,
as reported by Study Clinicians and/or collected from participants’ medical records.
The key secondary clinical outcome is symptom severity on days 2 to 4, as reported on Trial
Diary.
Other clinical secondary outcomes include:
1. Symptom severity and duration, length of time to return to usual activities, and antibiotic
and antiviral consumption within 28 days as reported by patient on Trial Diary.
2. Health-related quality of life measured by the EQ-5D-5L (age >16 years) or EQ-5D-Y (age
1–15 years)
3. Participant and clinician views (see Table 1)
4. Hospital admissions within 28 days
5. Consultations for respiratory infections within 6 months
6. Name and dose of antibiotics and antivirals prescribed within 28 days
Safety reporting
Site staff are responsible for recording appropriate adverse events (AEs) for the participants
during the trial. Only non-serious AEs that are assessed as being possibly, probably or defi-
nitely related to the intervention or trial procedures will be recorded in the relevant trial docu-
mentation. They should also be recorded in the participant’s medical notes by site team and
the participant should be followed up until the event resolves. Non-serious AEs that are unre-
lated to the intervention do not need to be recorded. The reporting framework for non-serious
AEs is shown in Fig 3.
Sites are also required to record all serious AEs (SAE) on the trial database. These should
also be recorded in the participant’s medical notes and should be followed up by the site until
the event resolves. Any SAEs which are assessed by the local Principal Investigator (PI) as
being related to the trial procedures and unexpected for the procedure are classed as Suspected
Unexpected Serious Adverse Reactions (SUSAR) and must be documented on the full SAE
report form and submitted within 24 hours of staff becoming aware of the event. As is propor-
tionate to the nature of the trial, only SUSARs will require expediting reporting to the Sponsor.
The reporting framework for SAEs is shown in Fig 4.
All SAEs will be further reported to the DMC as part of their oversight meetings.
Sample size
Antibiotic prescribing at the index consultation is the primary outcome measure. The largest
individual patient data meta-analysis to date [3] reported a total of 65% use of antibiotics in
patients in observational and experimental studies, across a wide spectrum of respiratory infec-
tions and patient groups, as we propose in RAPID-TEST.
Previous stewardship trials of POCTs have used varying minimum clinically important dif-
ference (MCID) definitions of absolute prescribing reductions, from 10% [29] to 20% [30],
with actual reductions observed of 15% [29] and 22%[30]. Since POCTRMs are expensive, we
selected a MCID of 15%.
Assuming an antibiotic prescribing rate of 60% in the control group, 244 participants per
group will allow a true reduction to 45% in the GP POCTRM test group to be detected with
90% power at 5% significance. A total randomisation target of 514 will allow for 5% attrition.
We have assumed a relatively large minimum clinically important difference due to the high
cost of POCTRM.
Statistical analysis
A detailed statistical analysis plan will be finalised and made publicly available ahead of the
completion of recruitment. In outline, the primary analysis will be of observed data and con-
ducted according to the intention to treat principle. A logistic regression equation will estimate
the causal association between the primary outcome of antibiotic prescribing and allocated
intervention group as an odds ratio, presented with 95% confidence interval and p-value. Fur-
ther covariates will include participant age and chronic lung disease (used to stratify randomi-
sation). Variations between participating GPs in prescribing tendency will be accommodated
as dummy variables to distinguish each GP. Sensitivity analyses will gauge the robustness of
the conclusions to different assumptions about any missing data. The above approach will be
adapted e.g. through the choice of a suitable regression model, to the secondary outcome vari-
ables such as symptom severity at 2 to 4 days.
Potential mechanisms of action, linking the intervention with the prescribing of an antibi-
otic will be investigated. A key potential mechanism is the result of the POCTRM test which
will be investigated in a logistic regression models with covariates including allocated group
(results inform the clinical decision or not), result (virus detected or not), and the interaction
between the two. The interaction term will capture any evidence that the test result is influenc-
ing the prescribing decision, rather than a non-specific effect of the POCTRM which is inde-
pendent of the result, and distinguish this effect from any underlying ability of GPs to
prescribe to those participants who will benefit from an antibiotic.
Study management
The study is managed by the Bristol Trials Centre and sponsored by University of Bristol. The
Trial Management Group (TMG) includes members responsible for the day-to-day manage-
ment of the trial, including the chief investigator, co-investigators, trial manager, statistician
and patient representatives. The role of the TMG is to monitor the progress and conduct of the
trial, including adherence to the trial protocol. The Trial Steering Committee (TSC) is made
up of representatives from the RAPID-TEST trial team and independent members approved
by the funder. The Data Monitoring Committee (DMC) consists of an independent medical
statistician and medical experts in the field also approved by the funder. The TSC and DMC
meet as required; at least once a year.
The RAPID-TEST Trial Management Group and Independent Steering Committee both
include PPI members. PPI members of these groups have provided feedback on Patient Infor-
mation Sheets provided to trial participants, contributed to draft reports to funders and over-
sight committee meetings, and have provided input to develop strategies to improve trial
diversity and inclusivity.
Trial status
The trial opened to recruitment on 28th November 2022 and is currently using protocol v3.0,
06 March 2023. The trial is recruiting well and recruitment is expected to finish within the
original timelines (by 30th September 2024).
Discussion
The ‘holy grail’ of antimicrobial stewardship is to ensure the minority of patients needing anti-
biotics are given the shortest course of the narrowest spectrum treatment possible, while pre-
venting unnecessary exposure among the majority unlikely to benefit. The vast majority of
stewardship interventions currently available aim to reduce overall prescribing [34], with only
a handful of validated tools available to support precision prescribing in primary care [35, 36].
Given that a significant proportion of RTIs managed in primary care are considered viral
[37–39], it is plausible that a POCTRM providing accurate results quickly could improve pre-
scribing. However, there is currently insufficient evidence regarding the safety, efficacy, or
mechanism of action, let alone clinical and cost effectiveness, to recommend use of POCTRMs
in primary care. Efficacy studies are urgently needed to address these issues using randomised
controlled designs, as well as qualitative methods to understand clinician and patients’ percep-
tions of the tests. One of the strengths of the RAPID-TEST trial is its randomised controlled
trial design, which will be delivered in NHS GP practices. This RCT will show whether using
multiplex POCTRMs in primary care could safely reduce the unnecessary use of antibiotics,
and the beliefs that sustain unnecessary use, thereby reducing the public AMR risk. The trial
will also show whether POCTRM use affects clinically relevant patient outcomes, antiviral pre-
scribing, re-consultations and future consultations for RTIs. Although the use of the test in the
intervention group slightly extends the initial consultation time, it is possible that this longer
consultation could reduce re-consultations in the future. Using a mixed-methos approach, the
trial will also provide further insight into behavioural changes, such as how the POCTRM
might influence clinician and patient beliefs and confidence in the treatment decision to
reduce antibiotic prescribing.
The authors acknowledge the trial’s limitations. Participants are unblinded when complet-
ing the Trial Diary, which could lead to bias in patient-reported outcomes, and there is no
cost-effectiveness analysis at this stage. The POCTRM used in the trial does not test for typical
Supporting information
S1 Appendix. Information provided to clinicians.
(DOCX)
S1 Checklist. SPIRIT checklist.
(DOCX)
S1 File. RAPID-TEST protocol v3.0 06Mar23.
(PDF)
S2 File. RAPID-TEST PIS v2.0 04Oct22.
(PDF)
S3 File. RAPID-TEST ICF v2.0 04Oct22.
(PDF)
S4 File. RAPID-TEST protocol v2.0 04Oct22 (original approved protocol).
(PDF)
Acknowledgments
The RAPID-TEST study is sponsored by the University of Bristol. The sponsor is responsible
for oversight of the RAPID-TEST study and will ensure the study is managed appropriately.
The study was designed and is delivered in collaboration with the Bristol Trials Centre, a
UKCRC-registered clinical trials unit.The authors would like to thank all research and clinical
teams involved in recruitment, coordination and data entry for this study. Particular thanks
are given to Katalin Bagi, Lynne Bradshaw, Emma Bridgeman, Rachel Brierley, Emily Brown,
Joanna Coast and Hayley Dash, Paul Roy, Hannah Thornton and Liang Zhu.
The authors would also like to acknowledge the Trial Steering Committee and Data Moni-
toring Committee members.
Author Contributions
Conceptualization: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul
Mitchell, Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Funding acquisition: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul
Mitchell, Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Methodology: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul Mitchell,
Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Project administration: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret.
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