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

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)

Effect of Early Treatment with Ivermectin among Patients with Covid-19

“…We conducted this randomized, adaptive platform trial for the investigation of the efficacy of repurposed treatments for Covid-19 among adult outpatients at high risk for hospitalization. 10 The trial was designed and conducted in partnership with local public health authorities from 12 cities in Brazil in order to simultaneously test potential treatments for early Covid-19 with the use of a master protocol. A master protocol defines prospective decision criteria for discontinuing interventions for futility, stopping owing to superiority of an intervention over placebo, or adding new interventions.…”

“…Interventions that have been evaluated in this trial thus far include hydroxychloroquine and lopinavir–ritonavir (both in protocol 1) 11 and metformin, ivermectin administered for 1 day, ivermectin administered for 3 days, doxazosin, pegylated interferon lambda, and fluvoxamine (all in protocol 2), as compared with matching placebos. The full trial protocol with the statistical analysis plan has been published previously 10 and is available with the full text of this article at NEJM.org.…”

“…The adaptive design trial protocol and the master statistical analysis plan (available with the protocol) provide details of the sample-size calculation and statistical analysis, including adapted approaches to sample-size reassessment. 10 In planning for the trial, we assumed a minimum clinical utility of 37.5% of ivermectin (relative risk difference vs. placebo) in order for the trial to have 80% power, at a two-sided type I error of 0.05, for a pairwise comparison with placebo assuming that 15% of the patients in the placebo group would meet the primary outcome. This calculation resulted in a planned enrollment of 681 patients in each group.…”

Inpatient Administration of Alpha-1-Adrenergic Receptor Blocking Agents Reduces Mortality in Male COVID-19 Patients

“…Furthermore, our findings are consistent with prior data ( 13 ). Ongoing randomized clinical trials of prazosin ( 20 ) and doxazosin ( 21 ) against a placebo among hospitalized COVID-19 patients will include women and provide more definitive data on the therapeutic value of α 1 -blockers.…”

“…These results augment the rationale for studying and repurposing α 1 -blockers as a COVID-19 therapeutic. Thus, we await the results of two ongoing randomized clinical trials ( 20 , 21 ) to definitively assess the effectiveness of alpha-1-blockers in protecting patients against COVID-19.…”