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

Gilmar Reis,Gordon H Guyatt,Craig R Rayner,Edward J Mills,Jamie I Forrest,Cameron Chernecki,Hinda Ruton,Alla V Glushchenko,Eduardo Augusto Dos Santos Moreira Silva,Daniela Carla Medeiros Silva,Sheila Sprague,Ofir Harari,Lehana Thabane,Paula Mckay,Kristian Thorlund

doi:10.12688/gatesopenres.13304.2

Abstract

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.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 mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

Highlights

There remains a need for an effective and affordable outpatient treatment for early COVID-19
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
There are no effective approved therapeutic interventions approved for the early treatment of SARS-CoV-21,9–11

Summary

Objectives

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. 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.

Use of the following medications in the last 14 days

Treatment

Subsequent visits

Findings

Discussion