Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19.

Bramante, Carolyn T.; Huling, Jared D.; Tignanelli, Christopher J.; Buse, John B.; Liebovitz, David M.; Nicklas, Jacinda M.; Cohen, Kenneth; Puskarich, Michael A.; Belani, Hrishikesh K.; Proper, Jennifer L.; Siegel, Lianne K.; Klatt, Nichole R.; Odde, David J.; Luke, Darlette G.; Anderson, Blake; Karger, Amy B.; Ingraham, Nicholas E.; Hartman, Katrina M.; Rao, Via; Hagen, Aubrey A.; Patel, Barkha; Fenno, Sarah L.; Avula, Nandini; Reddy, Neha V.; Erickson, Spencer M.; Lindberg, Sarah; Fricton, Regina; Lee, Samuel; Zaman, Adnin; Saveraid, Hanna G.; Tordsen, Walker J.; Pullen, Matthew F.; Biros, Michelle; Sherwood, Nancy E.; Thompson, Jennifer L.; Boulware, David R.; Murray, Thomas A.

doi:10.1056/nejmoa2201662

Cited by 243COVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 ResearchLong-Term Effects of COVID-19

Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19.

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Bramante, Carolyn T., Huling, Jared D., Tignanelli, Christopher J., Buse, John B., Liebovitz, David M., Nicklas, Jacinda M., Cohen, Kenneth, Puskarich, Michael A. +29 more·2022·New England Journal of Medicine

DOI 10.1056/nejmoa2201662PMC PMC9945922

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Abstract

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 SARS-CoV-2 vaccination and receipt of other trial medications. 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.).

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Two earlier US randomized trials of ivermectin 400 μg/kg also found this result.
“which was a result also observed in the 2 previous randomized trials of ivermectin 400 μg/kg in the US.6,16”
From Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial (2023) · cites this paper as [6]
Several large double-blind randomized trials have not shown a clinically meaningful benefit for ivermectin when the targeted dose was 400 μg/kg per day for three days.
“Multiple large double-blind randomized clinical trials have failed to identify a clinically meaningful benefit of ivermectin when used at a targeted dose of 400 μg/kg daily for 3 days.6,17”
From Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial (2023) · cites this paper as [6]

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Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids
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Self-citation

Authors: Bramante, C. T., Huling, J. D., Tignanelli, C. J., Buse, J. B., Liebovitz, D. M., Nicklas, J. M., Cohen, K., Puskarich, M. A., Belani, H. K., Proper, J. L., Siegel, L. K., Klatt, N. R., Odde, D. J., Luke, D. G., Anderson, B., Karger, A. B., Ingraham, N. E., Hartman, K. M., Rao, V., Hagen, A. A., Patel, B., Fenno, S. L., Avula, N., Reddy, N. V., Erickson, S. M., Lindberg, S., Fricton, R., Lee, S., Zaman, A., Saveraid, H. G., Tordsen, W. J., Pullen, M. F., Biros, M., Sherwood, N. E., Thompson, J. L., Boulware, D. R., & Murray, T. A.
Affiliations: University of Minnesota (US)
University of North Carolina at Chapel Hill (US)
Northwestern University (US)
ORCID: Bramante, Carolyn T.
Huling, Jared D.
Tignanelli, Christopher J.
Buse, John B.
Liebovitz, David M.
Nicklas, Jacinda M.
Puskarich, Michael A.
Belani, Hrishikesh K.
Proper, Jennifer L.
Siegel, Lianne K.
Klatt, Nichole R.
Odde, David J.
Anderson, Blake
Karger, Amy B.
Ingraham, Nicholas E.
Hartman, Katrina M.
Avula, Nandini
Reddy, Neha V.
Erickson, Spencer M.
Lindberg, Sarah
Lee, Samuel
Zaman, Adnin
Pullen, Matthew F.
Biros, Michelle
Sherwood, Nancy E.
Boulware, David R.
Murray, Thomas A.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2022-08-18
Volume: 387
Issue: 7
Pages: 599-610
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa2201662
PMC: PMC9945922
OpenAlex: W4292148078
Cited by: 242
References: 50
Citations by year: 2026: 19 · 2025: 31 · 2024: 63 · 2023: 94 · 2022: 35
FWCI: 27.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: UnitedHealth Group Foundation
Fast Grants
National Center for Advancing Translational Sciences (KL2TR002492, UL1TR002494)
National Institute of Diabetes and Digestive and Kidney Diseases (DK124654-01A1)
Rainwater Charitable Foundation
The Parsemus Foundation
Topics: Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
Keywords: COVID-19 pandemic, SARS-CoV-2, metformin, ivermectin, fluvoxamine, drug repurposing, antiviral therapy, disease progression prevention, hypoxemia, hospitalization, mortality, obesity, overweight, emergency department visits, COVID-19 vaccination
MeSH terms: COVID-19, SARS-CoV-2, COVID-19 Vaccines, COVID-19 Drug Treatment, Adult, Aged, Aged, 80 and over, Hypoxia, Double-Blind Method, Female, Humans, Ivermectin, Male, Metformin, Middle Aged, Obesity, Pregnancy, Pregnancy Complications, Infectious, Fluvoxamine, Overweight

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