Background The effect of metformin on preventing long-term COVID-19 symptoms among low-risk adults has not been studied. The objective of this study was to Assess metformin compared with placebo during acute SARS-CoV-2 infection on the presence of COVID-19 symptoms 180 days later.

Methods The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 2983 outpatient adults ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days were included from 90 sites. Participants were randomized to metformin (titrated to 1500 mg daily) or placebo for 14 days. Post-acute sequelae of SARS-CoV-2 or death (PASCD) was ascertained by asking whether participants had symptoms they attributed to COVID-19 on day 180. Secondary outcomes included clinician diagnosis of long COVID. For the primary outcome, the single-sided threshold for efficacy was 0.975.

Results Among 2983 participants, the median age was 47 years (interquartile range [IQR] 38–57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or SARS-CoV-2 vaccines. There were no deaths. Overall, 96 (3.2%) reported COVID-19 symptoms on day 90, 101 (3.4%) on day 120, and 79 (2.6%) on day 180. The covariate-adjusted risk of PASCD on day 180 was lower in the metformin group (−0.008; 95% credible interval [CrI] −0.022 to 0.006; posterior probability of efficacy [PPE] 0.83), compared with the placebo group with an adjusted risk ratio of 0.79 (95% CrI 0.474 to 1.230). The risk of clinician diagnosis of long COVID (secondary outcome) on day 180 was lower in the metformin group (−0.007; 95% CrI −0.015 to 0.001; PPE 0.96), with a relative risk of 0.495 (95% CrI 0.155 to 0.995).

Conclusions The posterior probability of efficacy for metformin preventing the primary endpoint did not exceed the prespecified threshold of 0.975 for declaring efficacy. Secondary outcomes were numerically better with metformin.

Bramante: Reports grants from the NIH outside the current work during the conduct of the study. Stewart: Reports grants from NIH NCATS during the conduct of the study; Grants from NIH outside the submitted work. Boulware: Reports grants from NIH during the conduct of the study. McCarthy: Nothing to report. Gao: Nothing to report. Rothman: Reports grants from NIH, PCORI, AHRQ, CDC, CardioHealth Alliance during the conduct of the study. Spouse owns stock in Moderna unrelated to the current work. Mourad: Nothing to report. Thicklin: Nothing to report. Cohen: Nothing to report. Garcia del Sol: Nothing to report. Shah: Nothing to report. Mehta: Nothing to report. Cardona: Nothing to report. Scott: Nothing to report. Ginde: Reports grants from NIH during the conduct of the study; Grants from NIH, CDC, DoD, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work. Castro: Reports institutional grant funding from NIH, ALA, PCORI, AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; Speaker/Consultant fees from Grant Funding, Genentech, Teva, Sanofi-Aventis; Consultant fees from Merck, Novartis, Arrowhead, OM Pharma, Allakos; Speaker honorarium from Amgen, AstraZeneca, GSK, Regeneron; Royalties from Elsevier all outside the submitted work. Jayaweera: Reports grants from NCATS during the study; Grants from Gilead, Pfizer, Janssen, and ViiV. advisory board fees from ViiV and Theratechnologies outside the submitted work. Sulkowski: Reports advisory board fees from AbbVie, Gilead, GSK, Atea, Antios, Precision Bio, Viiv, and Virion; Institutional grants from Janssen outside the submitted work. Gentile: Reports personal fees from Duke University for protocol development and oversight during the conduct of the study; grants from NIH outside the submitted work. McTigue: Reports grants from NIH to the University of Pittsburgh during the conduct of the study; Research contracts to the University of Pittsburgh from Pfizer, Eli Lilly, and Janssen outside the submitted work. Felker: Reports institutional research grants from NIH during the conduct of the study and from Novartis outside the submitted work. Collins: Reports grant funding from NHLBI and personal fees from Vir Biotechnology during the conduct of the study. Dunsmore: Nothing to report. Adam: Reports other from US Government Funding through Operation Warp Speed during the conduct of the study. Lindsell: Reports institutional grants from NCATS during the conduct of the study; Institutional grants from NIH, CDC, and DoD; Contract with institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, Abbvie, and Astra Zeneca, Biomeme, and Novartis outside the submitted work; Dr Lindsell has a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center. Hernandez: Reports grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer; Personal fees from AstraZeneca, Boston Scientific, Cytokinetics, Bristol Myers Squibb, and Merck outside the submitted work. Naggie: Reports grants from NIH, the sponsor for this study, during the conduct of the study; Institutional research grants from Gilead Sciences, AbbVie; Consulting fees from Pardes Biosciences; Scientific advisor/Stock options from Vir Biotechnology; Consulting with no financial payment from Silverback Therapeutics; DSMB fees from Personal Health Insights, Inc; Event adjudication committee fees from BMS/PRA outside the submitted work.

NCT04885530

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 is supported with CARES ACT and American Rescue Plan Act funds awarded through grants 3U24TR001608-05S4, 3U24TR001608-06S1 and 3U24TR001608-07S1 from the National Center for Advancing Translational Sciences (NCATS). Additional support for this study was provided by contract 75A50122C00037 from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority. Vanderbilt University Medical Center Clinical and Translational Science Award UL1TR002243 from NCATS supported the REDCap infrastructure.

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Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

WCG IRB gave ethical approval for this work.

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ACTIV-6 is a platform trial using shared placebos. On completion of the platform trial, when there is no risk of unblinding across study arms, the data will be made publicly available by depositing it in an approved data repository such as NHLBI BioData Catalyst.