Eligibility criteria
The study will include patients who meet all of the following criteria:
- Aged within the eligible range for the site (Table 1);
- Presenting with acute fever defined as having a temperature of >37.5°C or a history of fever within the last 7 days with no focus, or with suspected RTI;
- Lacking symptoms and signs of severe illness that require hospital admission or referral as assessed by the study clinicians;
- Informed consent for children under 18 years of age provided by parent/guardian; patient assent required for adolescents 18 years or older;
- Willing to provide blood and other samples and to adhere to study procedures explained in the information sheet/consent forms following the protocol;
- Available and willing to return for follow-up visit at the health facility on day 7 (+/- 2 days)
Patients are excluded from the study if they fail to meet any of the inclusion criteria listed above.
Data will also be gathered from healthcare workers and patients/caregivers for the qualitative components, where consent is provided.
Qualitative pre-intervention study
The qualitative study will be conducted to understand the contextual factors and behavioural determinants affecting adherence to prescriptions by patient/caregivers, and the associated communication about prescriptions by healthcare workers. The findings will inform the Training and Communication package which will be implemented as part of the clinical intervention arm consisting of diagnostic algorithms, POCTs, prescribing decision trees, clinic process flow, training, and communication on adherence to prescription. Further research using the capacity, opportunity and motivation (COM-B) model(20) together with the Theoretical Domains Framework (TDF)(21) during the recruitment phase, will investigate the wider behaviour change implications of adherence to prescription beyond the Training and Communication package, as well as the long-term effects of behavioural determinants for healthcare workers who choose to use the clinical algorithms, new point-of-care RDTs, and associated prescribing practices.
Interventions
The trial intervention will consist of 1. Diagnostic tests (Table 2); 2. Diagnostic and clinical algorithm (Figure 1); 3. Training and communication of healthcare workers and patients/caregivers; and 4. Clinic process flow.
1. Diagnostic tests
The diagnostic tests to be used in the intervention package (Table 2) will be selected based on local needs.
Non pathogen-specific POCTs:
- White blood cell total and differential counts (WBC/diff)
- Urine dipstick
- C-reactive protein (CRP)
2. Diagnostic and clinical algorithm
Healthcare workers will follow a country-specific algorithm for cases in the intervention arm, which takes into account the specific tests to be used at the site. A typical clinical algorithm is outlined in Figure 1. Notably, the decision on pathogen-specific diagnostic tests to use in each case was based on clinical presentation, which we have grouped into respiratory and non-respiratory signs and symptoms. In addition, clinical decisions in the intervention arm will be supported by CRP and WBC/diff POCT.
Figure 1. Outline of diagnostic and clinical algorithm.
RSV = respiratory syncytial virus; GAS = group A Streptococci; CRP = C-reactive protein; WBC/DIFF = white blood cells total counts / differential counts; Rx = treatment; ATB = antibiotic; Y = prescribe antibiotic; N = antibiotic prescription not warranted; P = antibiotic prescription possible if clinically indicated
3. Training and Communication package
Communication messages about adherence to prescription are delivered by healthcare worker(s) to the study patient or caregiver in the intervention arm. The method of delivery of the communication message will be site-specific, depending on the roles of different types of healthcare workers, and behavioural determinants identified in the qualitative analysis. Training is provided to healthcare workers to deliver the communication messages; together, the training and delivery of the messages make up the Training and Communication package developed for each site based on findings from the qualitative work identifying behavioural drivers of adherence to prescriptions. The delivery of the core communication message will be personalized to the individual patient (e.g. adjusting emphasis, but not message content), based information collected from the patient before clinical assessment.
4. Clinic process flow
At the majority of sites, the clinic process flow described below, closely follows the normal clinic flow, only with minor changes to speed up the process, such as mechanisms to minimize queuing.
Participant flow
The participant flow is shown in Figure 2. Patients presenting at the clinic will be pre-screened for fever and those meeting the study eligibility criteria will be enrolled in either the control or intervention arm of the study by simple, 1:1 randomization. Participants in both arms will be seen by clinicians who will collect patient histories and conduct clinical examinations.
Patients in the control arm will follow routine diagnostic and treatment procedures for acute febrile illness as outlined in each clinic. Patients in the intervention arm will first be asked to provide information on their attitude towards the use of antibiotics, and then undergo a provisional diagnosis (respiratory/non-respiratory). Samples will be taken from patients to be performed using POCTs and any other tests based on the provisional diagnosis and algorithm. An additional communication package to influence adherence to prescription will be provided by the study team (clinicians, pharmacist and/or nurses) before the patient leaves the facility.
All patients in both the intervention and control arms will be followed up on day 7 (+/-2) in the health facilities, to reassess their health status and prescription adherence.
Figure 2. Study participant flow
Patients who do not improve following the day of enrolment will need to visit the health facilities making an unscheduled visit before the day 7 (+/-2) follow-up visit for further assessment and management.
The package of POCTs provided in the intervention arm is considered to be an addition to tests provided in routine care. Therefore, where site routine protocols include the use of blood culture or other laboratory tests, these will also be conducted in the intervention arm (along with the normal practice in the control arm). Patients will return to the clinic for review of their prescription in light of these test results, following the normal schedule.
Strategies to improve and assess adherence
Patients and caregivers in the intervention arm (but not the control arm) will receive a communication message in support of adherence to the prescription, based on the local research findings described above. The method of delivery of the communication message will be site-specific, depending on the roles of different types of healthcare workers, and the behavioural determinants identified in the qualitative analysis.
The delivery of the core communication message will be personalised to the individual patient, (e.g. adjusting emphasis, but not message content), based on a small amount of information collected from the patient before clinical assessment.
All patients in both the intervention and control arms will be followed up on day 7 (+/-2) in the health facilities to reassess their health status and adherence to prescription. Information on adherence to prescription will be collected using qualitative in-depth interviews with the patient, and through pill counts (participants/caregivers will be asked to bring back packaging and remaining medicine on day 7). This includes assessing the behaviour of patients who were not prescribed medication to find out if they obtained any antibiotics or any other treatment, the reasons for this, and where the antibiotics or other treatment were obtained.
All enrolled participants (and caregivers, in case of children) will be reminded prior to departure on day 0 to visit the health facilities if their illness worsens before day 7. All participants who do not return on day 7 will be followed up via telephone to assess their well-being, and the need to return to the clinic for the end of study assessment. Where feasible and where consent was provided by study participants at enrolment, the investigators will conduct home visits if the patient is unable to return to the clinic for the day 7 follow-up visit.
Adherence to the diagnostic algorithm will be evaluated by reviewing the Case Report Forms (CRFs) to assess algorithm-driven use of POCTs and antibiotic prescriptions.
Study outcomes
The primary outcome measures are the point estimates of:
- The proportion of cases of acute febrile illness with favourable outcome (defined as being alive + no fever + resolution of day 0 symptoms) on day 7, in both arms.
- The proportion of antibiotic prescriptions for acute febrile illness in the two arms. Specifically, the study intends to detect a reduction (at least 30% from the baseline) in unnecessary antibiotic prescribing, without adversely affecting clinical outcomes. While antibiotic prescription rates are known at the study sites, outcomes are not currently known because patients are not routinely followed-up.
The secondary outcomes are:
- Proportion of patients prescribed antibiotics at clinics who describe adherence to prescription on day 7.
- Proportion of healthcare workers who adhered to new algorithm.
- Proportion of participants experiencing adverse events (see description in safety section).
Participant timeline
The schedule of events is described in Table 3.
Sample size estimation
The sample size calculations were based on criteria that would allow evaluation of antibiotic prescribing at each site.
The sample size was calculated for each country in order to detect a 30% difference (with a 95% confidence interval of +/- 5%) in the antibiotic prescription proportions compared with the initial proportion without the intervention, with a power of at least 80% to detect such a precision estimate (Figure 3). The minimal theoretical sample size obtained for each site (20) has been increased by 10% to allow for loss to follow-up.
Figure 3. Sample size chart
Estimates of the current proportion of patients prescribed antibiotics for acute febrile illnesses at different clinics in each country study were used as the basis to calculate the required sample size (Table 4).
Sample sizes are considered a minimum. Enrolment will continue after the sample size has been reached, through the 12 months of the intervention, to allow for seasonal variations.
Strategies for achieving adequate participation enrolment
We estimate, based upon clinic registries for the previous one or two years, that there will be adequate enrolment of participants in all of the sites.
Assignment of interventions
Enrolled patients will be randomized into either the intervention or the control arm. Patients in the intervention arm will be managed with a package of interventions (as detailed above) and patients in the control arm will be managed as per routine clinical practice.
Patients will be randomized centrally, by site, into the intervention or control arm in a 1:1 allocation ratio. Randomization codes will be prepared by the trial data manager based on the sample size estimates for each site, and will be sent prior to commencement of enrolment to each site.
Blinding and masking
Not applicable as this is an open label study.
Data management
All anonymized clinical participant data relating to the trial will be recorded in electronic CRFs created on the study sponsor’s online clinical trials platform (OpenClinica Enterprise Edition version 4.0). The sponsor will provide training on CRF completion prior to the start of the study. Electronic data capture (EDC) will be performed via eCRFs on android tablets in offline mode, to facilitate data entry at peripheral sites with limited internet connections, and synchronized daily at site research offices with verified, reliable internet connections. Paper CRFs will be available as back-up. Only authorized study personnel will have access to the CRFs. Consent forms containing patient identifying data will be retained at each site and kept in secure lockable cabinets in a secure room with restricted access.
Records and documents, including signed informed consent forms (ICF) pertaining to the conduct of this trial will be retained by the principal investigator for 10 years after trial completion, unless local regulations or institutional policies require a longer retention period.
Data quality
Training on the protocol, Good Clinical Practice (GCP), Good Clinical Laboratory Practice (GCLP) and the use of the diagnostic tests will be provided by the sponsor and University of Oxford. A laboratory manual, which describes all of the sample testing procedures, will be provided by FIND prior to the commencement of the trial. Detailed training on the EDC system will be provided by the data manager prior to first participant enrolment at each site. All of the POCT results will be photographed following a standard operating procedure. These photographs will be uploaded into the CRF to ensure the quality of the POCT data being recorded in the database and so that corrective procedures can be followed should there be any discrepancies between the laboratory staff and the monitor, since a patient’s ongoing care is based on these results. The sponsor will perform risk-based monitoring of this trial, and associated quality control checks in line with ICH GCP, and all applicable regulatory requirements.
Training on qualitative methods of data collection, analysis, and use of the behaviour change wheel(21) process will be provided by University of Oxford and/or onsite social science leads.
Statistical methods
Populations for statistical analyses:
Table 5 describes the study populations for the purposes of analyses.
Descriptive statistics
Descriptive statistics tables will be generated to summarize the characteristics of the participants. The number of participants included and excluded will be reported. Among the included participants, the information will be broken down by site, sex, and age group. Results will be reported either in absolute numbers (e.g. number of subjects in a group) or summarized by mean, median, standard deviation, minimum, maximum and quartiles.
Efficacy analyses
The point estimates of the study outcomes (percentage of antibiotic use, percentage reduction from baseline), with a 95% confidence interval based on the Wilson score interval, will be calculated for (1) clinical outcome (favourable or unfavourable), (1a) between-arms and (1b) between compliant and compliant patients within arms; and for (2) antibiotic use, also (2a) between-arms and (2b) within-arms.
Analysis of endpoints
The endpoints of the trial will be evaluated as follows:
- The proportion of cases with a favourable outcome in the two arms, in the mITT and PP population
- The proportion of compliant cases with a favourable outcome in the PP population
- The proportion of inappropriate antibiotic prescription in the PP population
- The antibiotic prescription rate in the two arms, in the mITT and PP populations
- The proportion of antibiotic/no antibiotic prescriptions with favourable/unfavourable outcomes
Other analyses
We will calculate the combined proportion of compliant participants with favourable outcomes and non-compliant participants with unfavourable outcomes within each arm.
Additionally, the ratio of the proportion of compliant participants with a favourable outcome versus the proportion of non-compliant participants with an unfavourable outcome will be reported as relative risk.
There is no planned interim analysis.
Data and safety monitoring board
Given that the clinical decision to prescribe or not prescribe antibiotics in the intervention arm of the study will be guided by the intervention package, there is a possibility that the diagnostic algorithm may fail to detect a need for antibiotics in some participants, thereby exposing them to the risk of getting worse from disease. It is also possible that routine procedures might expose patients to risks, such as those related to inappropriate use of antibiotics or missed diagnosis, which we will monitor, but we will not change the routine care for the patients in the control arm during the trial.
Therefore, we have established a data safety monitoring board (DSMB), composed of experts, many of whom are based in LMICs with experience in paediatrics, tropical infectious diseases, statistics, clinical trials and social science work.
The DSMB will evaluate ongoing safety data, assess the risks and benefits, and give recommendations on whether to continue, amend or stop the trial. The DSMB will review, at agreed intervals, the following data as they relate to the study progress and participant safety:
- Number of screened patients, by study site
- Number of included patients, by study site and by study arm
- Patients’ baseline characteristics
- Number of patients withdrawn and lost to follow-up, by study site and by study arm and reasons for withdrawal
- Number of serious adverse events (deaths and hospitalisations) by study arm
Safety reporting
ICH definitions of adverse events (AEs) in this study will be interpreted in light of the lack of testing for any new diagnostic or medicinal product.
We will capture untoward events occurring during the period under observation in order to understand if either approach (current practice vs. new package of interventions) might be associated with a risk to the patient’s welfare (e.g. unnecessary use of antibiotics that could cause AEs; conversely, a practice that denies a patient a treatment that was otherwise warranted).
Non-serious AEs are to be reported on the CRF. In addition, each site principal investigator will be responsible for reporting serious adverse events (SAE) to the sponsor (FIND) within 24 hours as well as to the Ethics Review Committee with which they are associated, depending on the local requirements.
Ethical approvals
The overall protocol has been approved by the Oxford University Tropical Research Ethics Committee (OxTREC number 52-19). Each of the country-specific protocols is also approved by national and/or institutional ethics committees in Burkina Faso, Ghana, Uganda, India, Nepal and Myanmar* (*final document pending at the time of writing).
Informed consent
Informed consent will be obtained by the healthcare workers/social scientists from all participants and/or their legally authorized representatives/caregivers prior to their participation in the study. Patient information sheets and consent forms have been developed in English and translated into local languages within the respective study sites. Participants or their parents/caregivers will be required to sign and date a statement of informed consent that meets the requirements of the ethics review committees.
A copy of the ICF(s) will be given to the participant or the participant’s parents/caregivers.
Confidentiality
Participants will be assigned a unique identifier or study number. Any participant records or datasets that are transferred to FIND will contain the identifier only; participant names and any information which would identify the participant will not be transferred.
The patient study number will be on all labels, data collection sheets and in the database to maintain confidentiality, including in the CRF. All documents relating to the clinical study will be stored securely electronically within Open Clinica and will only accessible by study staff and authorized personnel. The study will comply with the General Data Protection Regulation (GDPR), which requires that personal data must not be kept as identifiable data for longer than necessary for the purposes concerned. All qualitative data will be stored at the sites.
Access to data
Only trial staff in country will have access to the data for each country. Only FIND as study sponsor, and Oxford, as study collaborator, will have access to the anonymized data collected at all of the sites. FIND will perform the meta-analysis following the statistical analysis plan.
Ancillary and post-trial care
The study aims to evaluate clinical outcomes and antibiotic prescription rates for acute fevers 7 days post-enrolment, and does not provide specific therapeutic interventions beyond the marketed and approved medications which will be prescribed by the treating physicians based on either routine practice, or the new diagnostic package. For participants who experience complications from an acute febrile illness in either arm of the study, resources will be provided to manage these, in line with the national guidelines in each country.
Dissemination policy
The publication policy follows the ICMJE guidelines(22). Both the protocol and the study outcomes will be published in peer-reviewed, open-access journals, and the data will be made available. We intend to publish both the individual study results and the aggregated-data meta-analysis. We will also publish the qualitative methodologies and results for the study as a whole, as well as for the individual studies.
We also intend to prepare policy briefs and summaries as required for policy makers at both country and international level, in order to inform guideline development and policy.