biostudies-literatureBramante CTNational Center for Advancing Translational SciencesThe Parsemus FoundationNCATS NIH HHSNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNHLBI NIH HHSRainwater Charitable FoundationUnitedHealth Group FoundationNCI NIH HHSFast Grants599-610https://www.ebi.ac.uk/biostudies/studies/S-EPMC9945922biostudies-literatureUnknown387(7)<h4>Background</h4>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.<h4>Methods</h4>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 SARS-CoV-2 vaccination and receipt of other trial medications.<h4>Results</h4>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.<h4>Conclusions</h4>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.).The New England journal of medicineRandomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.PMC9945922DK124654-01A1K23 DK124654UL1 TR002494P01 CA254849UL1 TR002489UL1TR002494F32 DK123878U54 CA210190P30 DK048520KL2 TR002492K23 HL133604T32 HL007741KL2TR002492P30 DK124723Rypka KJLiebovitz DMCOVID-OUT Trial TeamDeng NPatel BRao VKuehl EAErickson SMThompson JWu BDunn ATFricton RBelani HKDatta SLuke DGZinkl LSherwood NEFricton RDJohnson DMParrens ESingh PTordsen WJTople TLBrea JIngraham NESherwood NSimmons LBramante CTProper JLZaman AReddy NVLindberg SBroedlow CASinelli IBuse JBMachicado RHendrickson AFNgonyama RChristensen GReddy NCampora PLee SKarger ABFraser DJTignanelli CJSaveraid HGCharles JJeng ACFairbairn FMZolik MRSnyder ANicklas JMOdde DJPullen MFMurray TAShahriar AKlatt NRFenno SLWatson RHBAvula NChristiansen TBoulware DRSeloadji PPuskarich MAHagen AAParra DLaBar DDHuling JDCohen KSiegel LKMohamud ZAtwater RCSiegart JLBeckman KBConnelly BStauffer MTAnderson BHartman KMThompson JLGriffiths GBiros MfalseRandomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.<h4>Background</h4>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.<h4>Methods</h4>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 SARS-CoV-2 vaccination and receipt of other trial medications.<h4>Results</h4>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.<h4>Conclusions</h4>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.).2022-01-01T00:00:00Z2022 Aug2026-05-28T17:46:57.642Z2025-04-04T11:27:16.711ZS-EPMC99459223607071010.1056/nejmoa220166210.1056/NEJMoa2201662