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Rapid respiratory microbiological point-of-care-testing and antibiotic prescribing in primary care: Protocol for the RAPID-TEST randomised controlled trial [1]

['Samantha Elizabeth Abbs', 'Bristol Trials Centre', 'Bristol Medical School', 'University Of Bristol', 'Bristol', 'United Kingdom', 'Lindsay Armstrong-Buisseret', 'Kathy Eastwood', 'Patient Representative', 'Stephen Granier']

Date: 2024-06

This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary care.

Qualitative interviews are being conducted with approximately 20 clinicians and 30 participants to understand any changes in beliefs and behaviour resulting from the point-of-care-test and generate attributes for clinician and patient discrete choice experiments.

This is a multi-centre, individually randomised controlled trial with mixed-methods investigation of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12 months and over presenting to primary care in the UK with a suspected respiratory tract infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, necessary. Once consented, all participants are asked to provide a combined nose and throat swab sample and randomised to have a rapid microbiological point-of-care-test or no point-of-care-test. For intervention patients, clinicians review the result of the test, before contacting the patient to finalise treatment. Treatment decisions are made as per usual care in control group patients. The primary outcome is whether an antibiotic is prescribed at this point. All swab samples are sent to the central laboratory for further testing. Patients are asked to complete a diary to record the severity and duration of symptoms until resolution or day 28, and questionnaires at 2 months about their beliefs and intention to consult for similar future illnesses. Primary care medical records are also reviewed at 6-months to collect further infection consultations, antibiotic prescribing and hospital admissions. The trial aims to recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute reduction in antibiotic prescribing.

Antibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite good evidence of there being no benefit to the patient, and evidence of over prescribing driving microbial resistance. The high treatment rates are attributed to uncertainty regarding microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as potential antibiotic stewardship tools, with some providing microbiological results in 15 minutes. However, there is little research on their impact on antibiotic use and clinical outcomes in primary care.

Funding: The trial was funded by the NIHR Efficacy and Mechanism Evaluation Programme (NIHR131758) that was awarded to Prof Alastair D Hay. LY is also funded by NIHR as a Senior Investigator and some of her time on this project may have been supported by the funding she received from the NIHR Applied Research Collaboration West and NIHR Health Protection Research Unit.

Data Availability: No data have been generated or analysed at the time of publication. A data availability statement will be made available after study completion.

Copyright: © 2024 Abbs et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 primary care practices in the south west of England.

Observational studies [ 23 , 24 ] have reported on the effects of POCT RMs 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 POCT RMs on antibiotic prescribing or clinical outcomes. We conducted a mixed-methods, observational feasibility study [ 25 ] which suggested a multiplex POCT RM was acceptable in primary care, and helped improve diagnostic certainty. However, none of these studies used randomised controlled trial methods, and none assessed the short- and long-term effects of POCT RM testing on clinician and patient beliefs and behaviour.

One potential solution to address this issue is point-of care-testing (POCT) in primary care settings. Rapid microbiological POCTs (POCT RMs ) 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 POCT RMs 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.

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 practitioners (GP) and primary care nurses [ 2 , 3 ], with 50% of these prescriptions considered inappropriate [ 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 ].

Material and methods

Design and setting This is a multi-centre, individually randomised controlled trial with a mixed-methods investigation of microbial, behavioural and antibiotic mechanisms, conducted in UK primary care. The trial is using eight POCT RM machines and recruiting from 16 GP (family doctor) practices across the South West of England, with eight sites recruiting participants per Winter. Sites with previous research experience and those who were confident they could deliver the relatively complex trial design were prioritised during site selection.

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: Aged ≥12 months on the day of presentation 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: Sore throat Runny nose Earache Cough Sputum Wheeze Shortness of breath Study Clinician diagnoses of an upper or lower RTI such as: Acute otitis media Acute sinusitis Acute pharyngitis or tonsillitis Sore throat Acute laryngitis Acute cough Acute bronchitis Chest infection Acute lower RTI Infective exacerbation of chronic lung disease e.g. asthma, chronic obstructive pulmonary disease (COPD), emphysema or bronchiectasis Study Clinician or patient/parent/carer believes antibiotic treatment is, or may be, necessary Patient/parent/carer willing and able to give informed consent 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 Study Clinician and patient/parent/carer willing to wait for the POCTRM result before an antibiotic prescribing decision is made 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 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: Known to have cystic fibrosis Require hospital admission Previously taken part in the RAPID-TEST RCT 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 Clinician 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 treatment 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 knowledge, 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 antibiotic prescribing and consumption.

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 BioFire® FilmArray® Torch 1 in conjunction with BioFire® RP2.1 plus reagent pouches (Biomerieux) according to the manufacturer’s instructions at the GP practice. The time for processing one swab to results being available is approximately 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/ Enterovirus (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 pneumoniae 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 prescribing 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 sample 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.

Control and central laboratory testing The remaining swab sample from all (intervention and control) participants is stored at ambient temperature at the GP practice prior to transfer to the central research laboratory (UKHSA South West Regional Laboratory, Southmead Hospital, Bristo) within 24 hours of collection. Samples not sent on the same day of collection are stored in the GP practice fridge (2 to 8°C) overnight. At the central laboratory, these samples are tested for the presence of respiratory viral and bacterial pathogens using a Taqman Low Density polymerase chain reaction array card assay [26] as well as the same BioFire® RP2.1 plus reagent pouches run on the Biofire® Filmarray® Torch 1 system used at the GP practices. At the end of the study any residual sample 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 validated 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 questionnaire 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.

Optional qualitative interviews and Discrete Choice Experiment (DCE) surveys During the consent process, participants (or parents/carers if the participant is <16 years) are asked whether they are interested in being contacted about taking part in an optional Participant Interview and receiving a separate optional Participant Discrete Choice Experiment (DCE) survey. Participants (or parents/carers if the participant is <16 years) can choose to be contacted about the interview and the DCE survey, just one, or neither. This does not affect their ability to take part in the main trial. Clinicians from each site are asked whether they are interested in being contacted about taking part in an optional Clinician Interview. In addition, Study Clinicians involved in the trial and other clinicians recruited through the West of England Clinical Research Network will be invited to complete a Clinician DCE survey. A DCE is a method commonly used in health economics to elicit stated preferences from health care stakeholders.[28] Participant and Clinician DCE surveys will be developed based on the qualitative interview findings with participants and clinicians, respectively.

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: 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. Health-related quality of life measured by the EQ-5D-5L (age >16 years) or EQ-5D-Y (age 1–15 years) Participant and clinician views (see Table 1) Hospital admissions within 28 days Consultations for respiratory infections within 6 months Name and dose of antibiotics and antivirals prescribed within 28 days

Data collection and management The data collection schedule is outlined in Fig 2. Data is directly entered onto a bespoke REDCap database and stored on a secure server, only accessible to authorised staff. Patient reported Trial Diary and questionnaire data are also recorded and stored on the trial database All study documentation will be retained in a secure location during the study and for at least 5 years after the end of the study. For children under the age of 16 at recruitment, research data will be kept until their 25th birthday. PPT PowerPoint slide

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TIFF original image Download: Fig 2. Schedule of enrolment, interventions and assessments. https://doi.org/10.1371/journal.pone.0302302.g002

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 infections and patient groups, as we propose in RAPID-TEST. Previous stewardship trials of POCTs have used varying minimum clinically important difference (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. If the POCTRM results in fewer antibiotic prescriptions, we wish to demonstrate non-inferiority of the POCTRM in terms of not increasing mean symptom severity at days 2 to 4 to a clinically significant extent. Assuming 80% completion of Trial Diaries (as previously achieved in adults [31] and children [32]) we will have data for symptom severity at 2 to 4 days in 206 participants per group. Data on 7,000 adults and children managed without POCT indicates a mean symptom severity at days 2 to 4 of 2.3 (standard deviation 1.5) [3]. We know this measure’s distribution is positively skewed and have used a calculation that accommodates this (assuming equal skew in both groups, quantified as a coefficient of variation of 0.7) [33]. Assuming, in truth, no difference between groups, 206 participants in each group will give 90% power for a one-sided 95% confidence interval to exclude increases in the average symptom score of 20% or more.

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 conducted 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. Further covariates will include participant age and chronic lung disease (used to stratify randomisation). 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 variables such as symptom severity at 2 to 4 days. Potential mechanisms of action, linking the intervention with the prescribing of an antibiotic 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 influencing the prescribing decision, rather than a non-specific effect of the POCTRM which is independent 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 management 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.

Patient and public involvement (PPI) Patients and members of the public have been involved in the design and management of this trial and will also be involved in dissemination activities. Multiple PPI meetings took place at the grant application stage and provided input into the final design on the trial. The RAPID-TEST Trial Management Group and Independent Steering Committee both include PPI members. PPI members of these groups have provided feedback on Patient Information Sheets provided to trial participants, contributed to draft reports to funders and oversight committee meetings, and have provided input to develop strategies to improve trial diversity and inclusivity.

Ethical considerations and dissemination The trial was approved by the North West—Preston Research Ethics Committee on 11th October 2022 (REC reference 22/NW/0294). Any amendments to the trial protocol will be approved by the Sponsor and ethics committee before implementing at sites. Written, informed consent (or verbal consent where written is not possible) to participate will be obtained from all participants (or the parent/carer if under 16 years old). A plan to disseminate the trial results will be developed by the TMG. The trial team plan to present findings at national and international meetings, and in peer-reviewed publications. Innovative methods of dissemination will be explored such as videos and blogs to accompany scientific papers that are accessible to the public, as well as providing a lay summary to participants.

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