Abstract
IMPORTANCE: The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied. OBJECTIVE: Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. DESIGN SETTING AND PARTICIPANTS: The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, 2991 participants age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days, were included at 90 US sites. INTERVENTIONS: Participants were randomized to receive metformin (titrated to 1500 mg daily) or placebo for 14 days. MAIN OUTCOMES AND MEASURES: The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving study drug. Secondary outcomes included time to hospitalization or death; time to healthcare utilization (clinic visit, emergency department visit, hospitalization, or death). Safety events of special interest were hypoglycemia and lactic acidosis. RESULTS: Among 2991 participants who were randomized and received study drug, the median age was 47 years (IQR 38-58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1443 participants who received metformin and 1548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR] 0.96; 95% credible interval [CrI] 0.89-1.03; P(efficacy)=0.11). For participants enrolled during current variants, the aHR was 1.19 (95% CrI 1.05-1.34). The median time to sustained recovery was 9 days (95% confidence interval [CI] 9-10) for metformin and 10 days (95% CI 9-10) for placebo. No deaths were reported; 111 participants reported healthcare utilization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81-1.75; P(efficacy)=0.135). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. Five participants in each group reported having hypoglycemia. CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, metformin was not shown to shorten the time to symptom resolution in adults with mild to moderate COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04885530 ).