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 conducted 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. Eligible 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 outcome was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to tertiary 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 probability 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 metformin 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 significant 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 hospitalization due to worsening COVID-19. There were also no differences between metformin and placebo observed for other secondary clinical outcomes.

COVID‐19 immunopathology: From acute diseases to chronic sequelae

“… 260 Likewise, metformin was not able to provide clinical benefits even given early. 261 These clinical observations failed to indicate any beneficial role of metformin. Nevertheless, in clinical trials involving COVID‐19 patients with type 2 diabetes, there appeared a reduced risk of mortality associated with the metformin treatment.…”

Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity

“…This placebo-controlled, randomized, clinical trial included 418 subjects, half randomized to taking metformin and half to placebo. There were no significant differences between the metformin and placebo groups on viral clearance through day 7 of illness and no difference in reducing emergency visits or reducing hospitalization for severe disease ( 71 ). This study suggests that acute administration of metformin may not be as beneficial as longer-term use of metformin.…”

Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of subsequent hospitalization and death compared to their non-prescribed peers: population-based matched cohort study

“…We assumed a hypothetical unmeasured confounding that "worked" to diminsh the (presumed) bene cial (risk-reducing) effect of uvoxamine. Speci cally, we assumed that among control subjects (Cohort B in Study 1, Cohort Paroxetine in Study 2), 40% were using some treatment (e.g., other antidepressant/anxiolytic, or any other) that was actually effective against COVID-19 with a marked effect of 30% reduction of the risk of disease deterioration (corresponds to the largest effect reported from RCTs of uvoxamine [2]), and that only 1% of the uvoxamine-exposed subjects were co-treated with such a treatment, and we corrected the observed estimates for this bias. 3): (i) < 1% of the patients in each cohort were fully vaccinated and 95% received no vaccination whatsoever; (ii) in Study 1, Cohort C patients (free of psychiatric di culties/treatments) appeared younger and had clearly lower prevalence of all comorbidities than Cohort A (psychiatric di culties, prescribed uvoxamine) and Cohort B (psychiatric di culties, not prescribed uvoxamine) patients, who were closely similar in all aspects (Table 3); (ii) in Study 2, patients in the two cohorts were closely similar in respect to all pre-COVID-19 characteristics, and were in this respect also similar to Cohort A and Cohort B in Study 1 (Table 3).…”