Abstract: T h e n e w e ng l a n d j o u r na l o f m e dic i n e Original Article Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 C.T. Bramante, J.D. Huling, C.J. Tignanelli, J.B. Buse, D.M. Liebovitz, J.M. Nicklas, K. Cohen, M.A. Puskarich, H.K. Belani, J.L. Proper, L.K. Siegel, N.R. Klatt, D.J. Odde, D.G. Luke, B. Anderson, A.B. Karger, N.E. Ingraham, K.M. Hartman, V. Rao, A.A. Hagen, B. Patel, S.L. Fenno, N. Avula, N.V. Reddy, S.M. Erickson, S. Lindberg, R. Fricton, S. Lee, A. Zaman, H.G. Saveraid, W.J. Tordsen, M.F. Pullen, M. Biros, N.E. Sherwood, J.L. Thompson, D.R. Boulware, and T.A. Murray, for the COVID-OUT Trial Team*​​ A BS T R AC T BACKGROUND Early 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. METHODS In 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 SARSCoV-2 vaccination and receipt of other trial medications. The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Dr. Bramante can be contacted at ­bramante@​­umn​.­edu or at the Division of General Internal Medicine and Pediatrics, University of Minnesota, MMC 1932, Minneapolis, MN 55414. *The members of the COVID-OUT trial team are listed in the Supplementary Appendix, available at NEJM.org. Drs. Boulware and Murray contributed equally to this article. N Engl J Med 2022;387:599-610. DOI: 10.1056/NEJMoa2201662 Copyright © 2022 Massachusetts Medical Society. RESULTS A 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. CONCLUSIONS None 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.) n engl j med 387;7 nejm.org August 18, 2022 The New..