Keywords
COVID-19; SARS-CoV-2, repurposed drugs, RCT, adaptive design, early treatment, outpatient care, master protocol
This article is included in the Coronavirus (COVID-19) collection.
COVID-19; SARS-CoV-2, repurposed drugs, RCT, adaptive design, early treatment, outpatient care, master protocol
Dear members of the Gates Open Research,
Thank you for the feedback on the TOGETHER Trial master trial protocol manuscript. For each peer reviewer’s comments, we provide a response and reference edits in the manuscript, where appropriate. Below is a summary as well of our changes:
In this version of the protocol manuscript we have answered each of the reviewers concerns point by point. We have made changes only to clarify points made by the reviewers. These points generally concerned giving more clarity to trial procedures. We have also aligned this version of the manuscript the protocol submitted for ethical approval and the statistical analysis plan. There was a concern that the abstract was too long in the revised manuscript. This is now shortened to less than 300 words as indicated. There were no changes made to the Tables or the Figure in this version of the manuscript. There are no changes to the author list or order of authors and no change to the manuscript title.
If you have any further questions, please do not hesitate to contact me.
Sincerely,
Dr. Edward Mills (for the authors)
See the authors' detailed response to the review by Christian Gluud and Anders Granholm
See the authors' detailed response to the review by Andrew Conway Morris
The discovery of effective and affordable treatments for preventing COVID-19 disease progression and subsequent hospitalization in outpatient settings is critical to minimize limited hospital resources, particularly for resource-limited settings1. As vaccine rollout has been slow in resource-limited countries and new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause concern for their effectiveness, identifying therapeutics that are affordable, widely available and effective against COVID-19 is of prime importance. Repurposing existing medications is an appealing approach as drugs currently used to treat other health conditions have known safety profiles.
There is also a need for more clinical trials in early infected populations. A majority of trials of repurposed drugs are conducted among inpatients with advanced clinical disease, yet the majority of COVID-19 cases are seen in the community setting2. Early treatment trials have the added benefit of evaluating drugs with the outcome of disease progression or hospitalization3. The TOGETHER Trial is an example of a global study network to evaluate repurposed drugs in early infected populations.
The TOGETHER Trial is an adaptive, multi-arm platform trial, evaluating multiple concurrent interventions (investigational products [IPs]) versus placebo among outpatients at high risk of developing COVID-19-related complications. The trial is designed to allow for multiple intervention arms to be implemented at any time and data to be merged with data from other external trials. This is a new approach for clinical trials that has occurred as a result of the COVID-19 pandemic and integrates platform adaptive trial designs with data synthesis to facilitate rapid decision-making. The overarching objective of this study is to test the hypothesis that repurposed drugs versus placebo effectively prevent worsening of COVID-19 requiring hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. This protocol is reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines4.
The TOGETHER Trial is an adaptive, multi-arm platform trial with equal allocation of interventions and placebo. The setting for the trial is 13 primary care and emergency department outpatient clinics in the Brazilian state of Minas Gerais.
The primary objective is to determine if each of the IPs reduces hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. The composite endpoint addresses both hospitalization and a proxy for hospitalization, retention in a COVID-19 emergency setting, as many patients who would be hospitalized were prevented from admission due to hospital over-capacity during peak waves. This region of Brazil implemented hospital-like services in the emergency settings with 50-80 bed settings and provides services including oxygenation, sedation, multi-day stays, and mechanical ventilation.
The secondary objectives are to evaluate, in comparison with placebo, the effect of the IPs on the following parameters: 1) viral clearance, 2) time to clinical improvement, 3) number of days with respiratory symptoms, 4) time to hospitalization for any cause or due to COVID-19 progression, 5) all-cause mortality and time to death from any causes, 6) WHO clinical worsening scale, 7) quality of life scale (PROMIS-10 scale), 8) Telephone Interview for Cognitive Status (TICS) memory assessment scale, 9) days in hospital and on a ventilator, 10) adverse events, 11) adverse reactions to IPs, and 12) adherence with IPs. All secondary outcomes are assessed up to 28 days following randomization.
Ethical review for this trial follows the Brazilian standard process of CEP/CONEP approval. The trial protocol is first reviewed by the local ethics review board in Brazil, followed by review at the national level by the National Committee for Ethics in Research (CONEP), since the trial is supported by international funding. CONEP approval number: 41174620.0.1001.5120. Research staff members located at the primary care or emergency department clinic where patients first present with symptoms are responsible for obtaining written informed consent. Prospective participants are read the informed consent form which describes trial procedures, potential risks, measures to protect their personal identity, and which parties will have access to their medical information. Ethics certificates from the CEP/CONEP approval process in Brazil are submitted to the Hamilton Integrated Research Ethics Board (HiREB) at McMaster University, which serves as the Ethics Board of Record, for final review and approval. HiREB project number: 13390.
The inclusion criteria are:
1. Patients 18 years and over with the ability to provide free and informed consent.
2. Patients presenting to an outpatient care setting with an acute clinical condition compatible with COVID-19 and symptoms beginning within 07 days from the randomization date.
3. Patients over 18 years and with at least ONE of the following criteria:
a) Age ≥ 50 years (does not need any other risk criteria)
b) Diabetes mellitus requiring oral medication or insulin
c) Systemic arterial hypertension requiring at least 1 oral medication for treatment
d) Known cardiovascular diseases (heart failure, congenital heart disease, valve disease, coronary artery disease, cardiomyopathies being treated, clinically manifested heart disease and with clinical repercussion)
e) Symptomatic lung disease and / or being treated (emphysema, fibrosing diseases)
f) Symptomatic asthma patients requiring chronic use of agents to control symptoms
g) Obesity, defined as BMI> 30 kg / m2 (weight and height information provided by the patient)
h) Transplant patients
i) Patient with stage IV chronic kidney disease or on dialysis
j) Immunosuppressed patients / using corticosteroid therapy (equivalent to a maximum of 10 mg of prednisone per day) and / or immunosuppressive therapy
k) Patients with a history of cancer in the last 5 years or undergoing current cancer treatment
l) Patients with documented fever at screening (>38°C)
m) Patients with at least one of the following symptoms: cough, dyspnea, pleuritic chest pain AND/OR myalgias with limited daily activities (to a maximum of 25% of enrollment)
4. Patients with a positive rapid test for SARS-CoV-2 antigen performed at the time of screening or patients with positive SARS-CoV-2 diagnostic test within 7 days of symptom onset.
5. Willingness to use the proposed investigational treatment and follow the research procedures.
6. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study and through 90 days after the last dose of study medication.
Participants who already have a positive reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2 at the time of screening and meet all the inclusion criteria in the survey will not need a new confirmatory test for COVID-19 and can be considered eligible for the randomization.
Patients who meet any of the following criteria are excluded:
1. Patients with acute respiratory condition compatible with COVID-19 treated in the primary care and with hospitalization need.
2. Patients with acute respiratory condition due to other causes.
3. Severe terminal illness irrespective of type or etiology.
4. Acute flu showing at least ONE of the criteria below:
5. Use of the following medications in the last 14 days:
6. Patients using serotonin reception inhibitors (Donepezil, Sertraline).
7. Pregnant or breastfeeding patients.
8. Surgical procedure or use of contrast planned to occur during treatment or up to 05 days after the last dose of the study medication.
9. Inability of the patient or representative to give informed consent or adhere to the procedures proposed in the protocol.
10. Known hypersensitivity and / or intolerance to IPs, or taking medications contraindicated by IPs.
11. Inability to follow protocol-related procedures.
Patients presenting to an outpatient clinic setting with clinical criteria for presumptive diagnosis of COVID-19 who meet the above eligibility criteria are invited to participate in the trial. Nurses, clinicians and health workers will obtain written informed consent from potential trial participants. After obtaining informed consent, research personnel collect demographic information and medical history, and confirm positivity for SARS-CoV-2 using the Abbott Panbio rapid antigen testing for previously undiagnosed patients.
Participants are randomized using a centralized randomization process which uses pre-prepared lists for each participating clinical site. Block sizes of 10 are used. Randomization is stratified by clinical site and participant age (< 50 years /≥ 50 years). At the time of randomization, clinical site personnel send a text message to the unblinded pharmacist at the coordinating center requesting to randomize a participant. The unblinded pharmacist at the coordinating center replies to the message within 5–10 minutes with the medication letter and randomization number. Allocation of treatment assignment is concealed from all other study personnel.
Different placebos may be used depending on which IPs are included. For example, if IPs are being administered in both pill format and by injection, participants randomized to the placebo group will be randomly assigned to receive a placebo pill or a placebo injection. If IPs of different duration are being used (e.g. 1 day, 3 days, 10 days, 14 days), participants randomized to the placebo group will also be randomized to different placebo regimens (e.g. 1 day, 3 days, 10 days, 14 days).
Randomization lists are prepared and kept confidential by an unblinded statistician and treatment packages are prepared by an unblinded pharmacist. With each newly eligible participant, the clinician contacts the unblinded pharmacist by WhatsApp to request a code that corresponds to a blinded treatment package. Data are unblinded at the time of the planned interim analyses and at the end of the trial. The trial is quadruple blinded, with participants, research personnel, sponsors, and designees. The Data and Safety Monitoring Committee (DSMC) do not have access to the patient's allocation during review of the interim analysis data, except in the foreseen situations (i.e., decision to stop a treatment arm, termination of the trial, or safety concerns).
The master protocol format and the adaptive design allows the easy addition of different IPs. Ethics approvals are obtained before adding a new IP. Participants are prescribed the IPs and corresponding placebo as indicated in the protocol. An unblinded pharmacist at each clinical site prepares the IP or placebo as per the randomization sequence. The IPs are shipped and stored in a temperature-controlled manner as per the requirements for each IP. Table 1 shows the previous, current (at the time of writing), and planned IPs of investigation in the TOGETHER Trial.
Investigational Product (IP) | Dose | Dosing schedule | Route of administration |
---|---|---|---|
Hydroxychloroquine* | 400mg | Two tablets on Day 1, then 1 tablet for 9 days | Oral |
Lopinavir/ritonavir* | 200/50mg | Four tablets twice a day on Day 1, then two tablets twice a day for 9 days | Oral |
Fluvoxamine Maleate | 100mg | One tablet every 12 hours for 10 days | Oral |
Ivermectin | 400 mcg/kg up to 90kg weight | 3–6, 6mg tablets (weight dependent) every 24 hours for 3 days | Oral |
Metformin Extended Release | 750mg | One tablet every 12 hours for 10 days | Oral |
Doxazosin | 2mg | Progressive dosing conditioned on SBP <120 mmHg; 0.5 tablet Day 1–2, 1 tablet Day 3–4, 2 tablets Day 5–7, 3 tablets Day 8–10, 4 tablets Day 11–14 | Oral |
Pegylated Interferon Lambda | 180 mcg in 0.45 mL | One injection at randomization | Sub-cutaneous injection in lower abdomen |
*Reis G, Moreira Silva E, Medeiros Silva DC, Thabane L, Singh G, Park JJH, Forrest JI, Harari O, Quirino Dos Santos CV, Guimaraes de Almeida APF et al: Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open 2021, 4(4):e216468.
Study data are collected on a paper record by the study staff member either in-person at the clinic or by WhatsApp video or voice call with the participant. Data are entered into the IBM electronic case report forms (eCRFs) at each study site. Data quality checks are first performed at the site level, and secondary data checks are performed by central research staff, located at the research coordinating office in the Minas Gerais capital of Belo Horizonte. Weekly meetings are held by Zoom with all study sites to provide feedback on data quality and completeness and continuous training is provided to each site following any changes to the eCRFs or other study procedural amendment. The CRFs can be found as extended data4.
The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19.
Secondary outcomes include: 1) viral clearance at days 3 and 7, 2) time to clinical improvement, 3) number of days with respiratory symptoms, 4) time to hospitalization for any cause or due to COVID-19 progression, 5) all-cause mortality and time to death from any causes, 6) WHO clinical worsening scale, 7) quality of life scale (PROMIS-10 scale), 8) Telephone Interview for Cognitive Status (TICS) memory assessment scale at day 28, 9) days in hospital and on a ventilator, 10) adverse events, 11) adverse reactions to IPs, and 12) adherence with IPs. All secondary outcomes are assessed up to 28 days following randomization.
The study activities for capturing these outcomes at each visit is displayed in Table 2 and Figure 1.
Screening Visit (D-0) | Baseline and Randomization (1) D-0 | Day 1 | Day 2(4) | Day 3(4) ± 1 day | Day 4 (4) | Day 5(4) | Day 7(4) ± 1 day | Day 10 ± 2 days | Day 14(4) ± 2 days | Day 28(4) ± 3 days | Day 60(4,8,9) or Early Termination ± 5 days | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Informed Consent | X | |||||||||||
SARS-CoV-2 Rapid Test | X(1) | |||||||||||
Eligibility Criteria Review | X(2) | |||||||||||
Pregnancy Test | X(3) | |||||||||||
Demographics | X(5) | |||||||||||
Co-morbidities and Risk Factors | X | |||||||||||
Medical History | X | |||||||||||
WHO Clinical Worsening Scale | X | X | X | X | X | X | X | X | X | X | X | |
Exposure to Index Case Information | X | |||||||||||
Substance Abuse | X | |||||||||||
PROMIS Global Health Scale | X(6) | X(6) | X(6) | X(6) | ||||||||
ECG | X | |||||||||||
Height and Weight | X | |||||||||||
Nasopharyngeal Swab | X | X | X | |||||||||
Randomization | X | |||||||||||
Concomitant Medications | X | X | X | X | X | X | X | X | X | X | X | |
Investigational Treatment Administration | X(7) | X(7) | X(7) | X(7) | X(7) | X(7) | X(7) | X(7) | ||||
Hospitalization / Emergency Room Visits | X | X | X | X | X | X | X | X | X | X | ||
Respiratory Symptoms | X | X | X | X | X | X | X | X | X | X | ||
Adverse Events | X | X | X | X | X | X | X | X | X | X | ||
Adverse Drug Reactions | X | X | X | X | X | X | X | X | X | X | ||
Vaccination Status | X | X | X | |||||||||
TICS scale - Memory Evaluation | X |
Legend
1. Screening and baseline visit: must be carried out at the same time when attending the outpatient setting. Rapid antigen test for COVID-19 at the screening visit. Day 1 visit should also be conducted on the same day as the screening and baseline visit. After completing the screening visit procedures at the baseline visit and present all inclusion / exclusion criteria, participants should be immediately randomized. The first dose of IP must be administered on the same day of randomization (immediately after randomizing). The study medication will be administered as prescribed. Patients must be observed for 30 minutes after the medication administration.
2. Patients can be included in the trial if they have a COVID-19 diagnosis at baseline visit and have less than 7 days of flu-like symptoms.
3. Only women of childbearing potential and / or potential to become pregnant. Women of childbearing potential must necessarily use contraception during the first 15 days of the trial.
4. Visits through telephone contact, video call, telemedicine are calculated from the randomization date.
5. After signing the Informed Consent Form.
6. Questionnaires must be completed BEFORE any procedures of the proposed visit. Only a person not related to the research can help the patient during the questionnaire. In telephone visits, the patient must respond directly, at the time of contact.
7. Maintain the administration of the IP according to schedule. Discontinue it if adverse events prevent the IP from continuing.
8. Assessment of late complications associated with COVID-19.
9. Unscheduled visits may also be conducted as needed. The clinical outcome data collected at the unscheduled visit should be entered at the next scheduled visit. The treatment period is up to 14 days.
COVID-19=coronavirus disease 2019, SARS-CoV-2=severe acute respiratory syndrome coronavirus 2, WHO=World Health Organisation, ECG=electrocardiogram, TICS=Telephone Interview for Cognitive Status.
All participants receive standard treatment for COVID-19 as adopted by the health units to which they are linked, as defined by the medical assistant team. All participants will also receive 24-hour telephone contact number which they can call if they have any questions about the trial, if their condition worsens, or if they experience an adverse event. The first quarter of participants enrolled into each treatment arm will self-collect nasal swab and saliva for RT-PCR on day 3 and day 7 after randomization. Participants are instructed on this home sample collection and on the logistics for sample retrieval from their residence by study personnel.
The majority of patient evaluations are carried out by telephone contact, social media apps (e.g. WhatsApp), video calls or telemedicine. Face-to-face visits are limited as the virus is highly transmissible. Participants will follow the local health authorities’ guidelines regarding isolation and quarantine requirements, which are generally 14 days from a positive COVID-19 test. Only the day-14 visit will be conducted face-to-face to enable study personnel to collect the medication kits for drug accountability and treatment compliance.
A number of procedures are implemented to maximize participant retention. An informative video recorded by the principal investigator and take-home flyer encourages patients to adhere to study procedures and complete the trial. Participants are also sent occasional notification reminders on WhatsApp encouraging trial participation and follow-up appointments by WhatsApp are conducted in an effort to minimize travel days to the clinic.
By Brazilian regulations, we provide medical care to all patients throughout their participation (2 months). For longer term events, the trial insurance covers any study related adverse event for a period of three years post-randomization.
A Steering Committee and an independent DSMC have been established. The Steering Committee oversees the study to ensure scientific integrity and routinely assess emerging evidence to recommend interventions of interest for the trial. The Data and Safety Monitoring Committee oversees the safety of the research participants and reviews the results of each interim analysis and final analysis and makes recommendations on stopping or continuing each IP. Events of special interest flagged by the Data and Safety Monitoring Committee are followed-up by study physicians.
Members of the Data and Safety Monitoring Committee include: Dr James Orbinski of York University (Canada), Dr Sonal Singh of University of Massachusetts (USA), and Dr. Jonas Haggstrom of Cytel Inc. (Sweden). Dr. Kristian Thorlund of McMaster University (Canada) serves as the non-voting chair of the Data and Safety Monitoring Committee.
The trial is a platform adaptive trial design with three planned interim analyses at approximately 25%, 50%, and 75% of the total required sample size. The initial sample size calculation is based on the test for the hypothesis that each of the IPs will be better than placebo in reducing hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. (defined above). The sample size of 681 patients per arm was chosen for each experimental group to achieve 80% power with 0.05 two-sided Type 1 error for a pairwise comparison against the control to detect minimum treatment efficacy defined by 37.5% relative risk reduction (RRR) of preventing hospitalization assuming a control event rate (CER) of 15%.
Sample size re-assessment will be performed, subject to the DSMC’s approval, if after the third interim analysis the control event rate appears to be considerably lower to the one the original sample size calculation was based on, irrespective of the observed RRR. In that event, we will rerun the simulation based on the new sample size calculated and with the first three interim analyses taking place as originally planned, to confirm that no type I error rate inflation is occurring. Should the efficacy criterion at the final analysis be modified to ensure that, any further change to the original design will be documented and reported.
Interim efficacy analyses are scheduled. Assuming a uniform prior assigned to the different event rates, a total sample size of 681 patients per arm, a CER of 15%, and a RRR equals to 37.5%, an interim analysis will be performed after observing approximately 25%, 50% and 75% of the maximum number of patient outcomes, as well as at the trial completion. The posterior efficacy threshold to stop for superiority is 97.6% and the futility threshold is 20%, 40% and 60% at the respective interim analyses. Intervention arms(s) showing a posterior probability of efficacy crossing either boundary, will be stopped for either reason. These superiority and futility thresholds were determined based on 200,000 simulation run ins wherein different values of the RRR were considered (0%, 20%, and 37.5%). A description of this interim analysis in an event-based Bayesian adaptive trial and accompanying illustrating example can be found in the appendix of this document.
When other data from other relevant studies become available, we will use Empirical Bayes meta-analysis5 to borrow information from the treatment effects or safety signals emerging from these studies. This is effectively a random effect Bayesian model that results in simultaneous shrinkage of the treatment effect or safety estimates reported in the various studies toward the meta-analysis estimate, while still providing standalone estimates. Schoenfeld et al. have shown6 that this approach is, in some ways, equivalent to the power prior approach of Chen and Ibrahim7, whereby historical studies are assigned fractional weight(s) whose magnitudes correspond to the consistency of their data with that of the study they are thought to inform. The analyses incorporating external evidence will be presented to the DSMC as secondary findings to consider but will not alone trigger a recommendation for a trial adaptation.
A detailed description of the TOGETHER Trial statistical analysis plan can be found in the extended data4.
In brief, the efficacy of each intervention will be analyzed in terms of its posterior efficacy with respect to placebo, using the Bayesian paradigm, while calibrating the decision boundaries to meet the type I error rate requirements. We will adopt an intention-to-treat principle to analyze all results. For descriptive statistics, multiple imputation will be employed where baseline covariates with up to 20% missing values among age, sex, race, BMI, time since disease onset and comorbidities, using the Multiple Imputation by Chained Equations (MICE) algorithm. However, adjustment to covariates - and subsequent pooled - analysis in the outcome model will only include covariates whose distribution appears to be imbalanced across the treatment arms.
We will validate the proportional hazards assumption by visually inspecting Kaplan-Meier and log-negative-log of survival plots and fit Cox model for time-to-event outcomes. Secondary outcomes, such as viral clearance will be modelled using a longitudinal logistic model with a subject random effect, using the PCR test result over time as our dependent variable.
Subgroup analyses
We will perform subgroup analyses to assess the consistency of effects in four patient subgroups:
We hypothesize that younger patients will benefit more than older patients, women will benefit more than men, patients with an earlier diagnosis will benefit more than those with a later diagnosis, and patients without the clinical co-morbidities described above will benefit more than those with these co-morbidities. All the subgroup hypotheses are based on data emerging from other countries, indicating the differential impact of COVID-19 by age, sex and the existence of clinical comorbidities at baseline conditions.
Data from the IBM eCRFs are securely sent by File Transfer Protocol (FTP) to the statistical team in SAS format. SAS v9.4 is used to convert raw data into an analytic dataset applying CDISC standards. Analyses are conducted using R v4.0.3. Results will be reported following the CONSORT guidelines.
The funder of this trial had no role in study design, data collection, decision to publish, or preparation of the manuscript.
The final trial dataset will be accessible by written request to the study principal investigators (G Reis or EJ Mills). There are no contractual agreements to limit access to final trial data. All data collected by the TOGETHER Trial will be shared with the International COVID-19 Data Alliance. Access to these data through the ICODA Workbench will follow the standard operating procedures developed by the ICODA working group.
Findings will be disseminated in several ways. All investigations of IPs vs. placebo will be submitted to an appropriate, peer-reviewed scientific journal. Lay summaries of findings will be made available on the TOGETHER Trial website (togethertrial.com). The investigative team is also connected to the WHO COVID-19 guidelines committee, where trial findings will help inform global clinical guidance.
The TOGETHER Trial has randomized more than 3700 patients to date. The trial has previously evaluated the effect of hydroxychloroquine or lopinavir/ritonavir on risk of hospitalization8. Investigations evaluating metformin, ivermectin, and fluvoxamine have been completed and manuscripts are under-development. Investigations are continuing for doxazosin and pegylated interferon lambda. The IPs of investigation in the TOGETHER Trial and their study status at the time of writing is further described in Table 1.
Our TOGETHER trial is innovative in a number of ways. First, from a clinical perspective, we are examining the use of drugs that would be widely available and accessible if proven effective and safe for the treatment of COVID-19. Second, our trial uses a new methodological approach adaptable to both internal accumulating data, as is common in platform trials, as well as incorporating external trial evidence that may be unplanned at the time of initial study launch.
Currently, there are no effective approved therapeutic interventions approved for the early treatment of SARS-CoV-21,9–11. Proposed therapies for SARS-CoV-2 are based on previous clinical experience directed against SARS-CoV-1 and Middle East respiratory syndrome (MERS)12. These therapeutic modalities consisted of viral methyl transferase inhibitors, protease inhibitors, interferon, inhibitors of viral ribonucleic acid (RNA) synthesis as well as anti-inflammatory drugs. For the treatment of COVID-19, there has been much promise and excitement for repurposing drugs that have similar targets described for SARS-CoV-1 and MERS1,13. The current use of repurposed drugs for COVID-19 treatment offers several key advantages as these medicines have been proven safe, their pharmacokinetics are well understood, and optimal dosages are standardized. Although hydroxychloroquine is ineffective for the treatment of COVID-19 among hospitalized adults14, other repurposed drugs have already shown promise against COVID-19 disease at the later stages of disease. Both dexamethasone and tociluzimab appear to significantly increase survival according to findings from the UK RECOVERY trials15. Furthermore, other new molecules such as remdesivir and monoclonal antibodies have had inconsistent findings16,17. Unfortunately, well-designed studies on asymptomatic or mild, or pediatric cases of COVID-19 are lacking. Neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes in early symptomatic COVID-19 patients8. In a preliminary study of adult outpatients with early COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days18. In another recent trial of favipiravir, an RNA-dependent RNA polymerase inhibitor, also did not show any statistically significant benefit in term of mortality in the general group of patients with mild to moderate COVID-1919. It was suggested that the use of antivirals in symptomatic patients is too late and would explain their low efficacy in the clinical setting. A number of clinical trials (NCT04426695, NCT04425629, NCT04479631) have now been initiated to assess safety, tolerability, and efficacy of SARS-CoV-2 neutralizing monoclonal antibodies (nMAbs) using either a prophylactic or therapeutic approach20–22. In addition, potent human monoclonal antibodies against SARS-CoV-2 have been isolated from COVID-19 convalescent patients which could provide another layer of therapeutic options against the disease23. Thus, by blocking acute virus replication, early nMAb intervention would potentially induce a better clinical outcome against COVID-19.
Our study has several limitations. The greatest limitation of our study is that the administrative stages of conducting a trial, from protocol development and ethics review to obtaining study drug and creating electronic case report forms are all reliant on the local infrastructure and norms of study conduct in those settings. Our adaptive elements of the trial complicate what is understood by some agencies and push-back from approval bodies has previously delayed enrolment. The rapid change in the scientific interest or confidence in interventions means that an application submitted to a funding agency or ethics committee, may, by the time it is reviewed, have changed dramatically. In addition, the generalizability of this trial is limited to patients who do not have severe terminal illness irrespective of type or etiology. Strengths of our study include the adaptive nature of the study to change arms by dropping or adding arms as the data, both internal and external. Our design permits outside data, from either trial we already collaborate with or trials with emerging data we learn of as we are conducting our trial. Similarly, outside evidence in the form of completed trials, may provide sufficiently compelling evidence to change the direction of our trial or change outcomes and interpretation of trial findings.
Our design is adaptive and also Bayesian in its learning structure and analysis. We refer to this as a learning structure as emerging data from our own trial will, almost certainly be influenced from data we were unaware of at the study outset. We are already learning of similar trials examining similar interventions (in at least one arm) where the population inclusion criteria and the outcomes can be harmonized with our dataset. Similarly, we may find out about completed trials that have convincing evidence that mandates a change in our trial. For example, if a large study with a similar population and outcome found overwhelming evidence of a treatment effect (whether that is harm, futility, or benefit), we may examine our data to confirm that the direction of treatment effect is similar. This may take the form of matching the population using a strategy such as propensity scoring or combining in a meta-analysis.
Results from this trial will help identify repurposed therapeutics for COVID-19 that can easily be scaled in low- and middle-income settings. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence will be the first of its kind and may prove highly valuable for all COVID-19 trials and trials for other indications going forward.
Open Science Framework: A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial. https://doi.org/10.17605/OSF.IO/EG37X4.
This project contains the following extended data:
Open Science Framework: SPIRIT checklist for ‘A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol’. https://doi.org/10.17605/OSF.IO/EG37X4.
Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
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References
1. Reis G, Silva E, Silva D, Thorlund K, et al.: A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol. Gates Open Research. 2021; 5. Publisher Full TextCompeting Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Molecular diagnostics, pneumonia diagnostics, critical care, neutrophil biology
Is the rationale for, and objectives of, the study clearly described?
Yes
Is the study design appropriate for the research question?
Partly
Are sufficient details of the methods provided to allow replication by others?
Partly
Are the datasets clearly presented in a useable and accessible format?
Not applicable
References
1. Tong A, Baumgart A, Evangelidis N, Viecelli A, et al.: Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery. Critical Care Medicine. 2021; 49 (3): 503-516 Publisher Full TextCompeting Interests: No competing interests were disclosed.
Reviewer Expertise: Molecular diagnostics, pneumonia diagnostics, critical care, neutrophil biology
Is the rationale for, and objectives of, the study clearly described?
Yes
Is the study design appropriate for the research question?
Partly
Are sufficient details of the methods provided to allow replication by others?
Partly
Are the datasets clearly presented in a useable and accessible format?
Not applicable
References
1. Reis G, Moreira Silva E, Medeiros Silva D, Thabane L, et al.: Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19. JAMA Network Open. 2021; 4 (4). Publisher Full TextCompeting Interests: No competing interests were disclosed.
Alongside their report, reviewers assign a status to the article:
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Version 1 05 Aug 21 |
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Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
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