• Carolyn T Bramante, Jared D Huling, Christopher J Tignanelli, John B Buse, David M Liebovitz, Jacinda M Nicklas, Kenneth Cohen, Michael A Puskarich, Hrishikesh K Belani, Jennifer L Proper, Lianne K Siegel, Nichole R Klatt, David J Odde, Darlette G Luke, Blake Anderson, Amy B Karger, Nicholas E Ingraham, Katrina M Hartman, Via Rao, Aubrey A Hagen, Barkha Patel, Sarah L Fenno, Nandini Avula, Neha V Reddy, Spencer M Erickson, Sarah Lindberg, Regina Fricton, Samuel Lee, Adnin Zaman, Hanna G Saveraid, Walker J Tordsen, Matthew F Pullen, Michelle Biros, Nancy E Sherwood, Jennifer L Thompson, David R Boulware, Thomas A Murray, and COVID-OUT Trial Team.
• From the Departments of Medicine (C.T.B., N.E.I., K.M.H., A.A.H., B.P., S.L.F., N.A., N.V.R., S.M.E., H.G.S., M.F.P., D.R.B.) and Surgery (C.J.T., N.R.K.), Emergency Medicine (M.A.P., M.B.), and Laboratory Medicine and Pathology (A.B.K.), Medical School, the Divisions of Biostatistics (J.D.H., J.L.P., L.K.S., V.R., S. Lindberg, T.A.M.) and Epidemiology and Community Health (N.E.S.), School of Public Health, and the Department of Biomedical Engineering (D.J.O.), University of Minnesota, the Department of Emergency Medicine, Hennepin County Medical Center (M.A.P., W.J.T., M.B.), and the Investigational Drug Service Pharmacy, University of Minnesota-Fairview (D.G.L.), Minneapolis, and UnitedHealth Group, Optum Labs, Minnetonka (K.C.) - all in Minnesota; the Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill (J.B.B.); the Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (D.M.L., R.F., S. Lee); the Department of Medicine, School of Medicine, University of Colorado-Anschutz Medical Campus, Aurora (J.M.N., A.Z.); the Department of Medicine, Olive View-University of California, Los Angeles (H.K.B.); Atlanta Veterans Affairs Medical Center and the Department of Medicine, Emory University School of Medicine - both in Atlanta (B.A.); and the Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville (J.L.T.).
• N. Engl. J. Med. 2022 Aug 18; 387 (7): 599610599-610.

BackgroundEarly treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.ResultsA total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.ConclusionsNone of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).Copyright © 2022 Massachusetts Medical Society.

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