Carolyn T Bramante, Thomas G. Stewart, David R Boulware, Matthew W. McCarthy, Yue Gao, Russell L. Rothman, Ahmad Mourad, Florence Thicklin, Jonathan B. Cohen, Idania T Garcia Del Sol, Nirav S Shah, Manisha Mehta, Orlando Quintero Cardona, Jake Scott, A A Ginde, Mario Castro, DT Jayaweera, Mark Sulkowski, Nina Gentile, Kathleen McTigue, G Michael Felker, Sean Collins, Sarah E. Dunsmore, Stacey J. Adam, Christopher J. Lindsell, Adrian F Hernandez, Susanna Naggie, for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators, Clyde Yancy, Adaora Adimora, Susan Ellenberg, Kaleab Abebe, Arthur Kim, J Lantos, Jennifer Silvey-Cason, Frank Rockhold, Sean O’Brien, Frank Harrell, Zhen Huang, Renato Lopes, W Schuyler Jones, Antonio Gutiérrez, Robert Harrison, David Kong, Robert McGarrah, Michelle Kelsey, Konstantin Krychtiuk, Vishal Rao, M A Hamm, Kirk T. Phillips, Andrew Vasey, Talethia Edwards, Danielle Nelson, Greg Merritt, Jeannie Nguyen, Josh Denson, Jonathan Arnold, Allison DeLong, R.B. Wilder, Ryan Fraser, Mark Ward, S. Weaver, M Patricia McAdams, Kayla Korzekwinski, Martina Oyelakin, Samantha Dockery, RODNEY ADKINS, Mathew Crow, Shanee Light, Renée Morris, Erin Nowell, Kadie Wells, Alicia Herbert, Allegra Stone, Heather Heavlin, Linley Brown, Shelley Brunson, Tina Harding, Amanda Harrington, Meaghan Beauchaine, Kelly Lindblom, Andrea Burns, Hayley Nemeth, Brad Kolls, Cina Sasannejad, Rajendra (Raj) Mehta, Mark Kittipibul, D Aamodt, Deborah Clark, Jess Collins, S Dixon, John Graves, James Grindstaff, Jessica Lai, Vicky Liao, Itzel Lopez, Elizabeth Manis, Kalley Mankowski, Jessica Marlin, Alyssa Merkel
BACKGROUND: We conducted a quadruple-blinded, randomized, placebo-controlled trial of metformin for treating acute SARS-CoV-2 infection to prevent long COVID symptoms in low-risk adults. 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 were included within 7 days of symptom onset from 90 sites. Participants were randomized to metformin 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-diagnosed long COVID. RESULTS: The median age was 47 years (interquartile range 38-57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or ≥2 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 adjusted risk of symptoms on day 180 was 0.8 percentage points lower with metformin (95% credible interval [CrI] -2.2 to 0.6) with a posterior probability of efficacy [PPE] for preventing symptoms of 0.83, risk ratio 0.79 (95% CrI 0.474 to 1.230). Compared with placebo, the risk of clinician-diagnosed long COVID was 0.7 percentage points lower with metformin (95% CrI -1.5 to 0.1); PPE 0.96; risk ratio 0.495 (95% CrI 0.155 to 0.995). CONCLUSIONS AND RELEVANCE: In low-risk adults, most with prior immunity, metformin did not exceed the efficacy threshold of 0.975 for PASC. Metformin reduced the risk of clinician-diagnosed long COVID.