Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19 : the together randomized platform clinical trial.

Abstract

Background Observational studies have postulated a therapeutic role of metformin in treating COVID-19. We con- ducted an adaptive platform clinical trial to determine whether metformin is an effective treatment for high-risk

patients with early COVID-19 in an outpatient setting.

Methods The TOGETHER Trial is a placebo-controled, randomized, platform clinical trial conducted in Brazil. Eligi- ble participants were symptomatic adults with a positive antigen test for SARS-CoV-2. We enroled eligible patients

over the age of 50 years or with a known risk factor for disease severity. Patients were randomly assigned to receive

either placebo or metformin (750 mg twice daily for 10 days or placebo, twice daily for 10 days). The primary out- come was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to ter- tiary hospital due to COVID-19 at 28 days post randomization. Secondary outcomes included viral clearance at day

7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to determine proba- bility of success of the intervention compared to placebo.

Findings The TOGETHER Trial was initiated June 2, 2020. We randomized patients to metformin starting January 15,

2021. On April 3, 2021, the Data and Safety Monitoring Committee recommended stopping enrollment into the metfor- min arm due to futility. We recruited 418 participants, 215 were randomized to the metformin arm and 203 to the placebo

arm. More than half of participants (56.0%) were over the age of 50 years and 57.2% were female. Median age was 52 years. The proportion of patients with the primary outcome at 28 days was not different between the metformin and

placebo group (relative risk [RR] 1.14[95% Credible Interval 0.73; 1.81]), probability of superiority 0.28. We found no sig- nificant differences between the metformin and placebo group on viral clearance through to day 7 (Odds ratio [OR],

0.99, 95% Confidence Intervals 0.88−1.11) or other secondary outcomes. Interpretation In this randomized trial, metformin did not provide any clinical benefit to ambulatory patients with

COVID-19 compared to placebo, with respect to reducing the need for retention in an emergency setting or hospital- ization due to worsening COVID-19. There were also no differences between metformin and placebo observed for

other secondary clinical outcomes.