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Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19.
Open accessAbstract
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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“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]
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“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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1 retracted
Reis, G., Silva, E. A. D. S. M., Silva, D. C. M., Thabane, L., Milagres, A. C., Ferreira, T. S., dos Santos, C. V. Q., Neto, A. D. D. F., Callegari, E. D., Savassi, L. C. M., et al. (2021) · The Lancet Regional Health - Americas · doi:10.1016/j.lana.2021.100142 · Cited by 65
RetractedA SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Gordon, D. E., Jang, G. M., Bouhaddou, M., Xu, J., Obernier, K., White, K. M., O’Meara, M. J., Rezelj, V. V., Guo, J. Z., Swaney, D. L., et al. (2020) · Nature · doi:10.1038/s41586-020-2286-9 · Cited by 4,405
(2020) · PubMed · Cited by 2,642
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19
Hammond, J., Leister-Tebbe, H., Gardner, A., Abreu, P., Bao, W., Wisemandle, W., Baniecki, M., Hendrick, V. M., Damle, B., Simón-Campos, A., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2118542 · Cited by 2,323
Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients.
Jayk Bernal, A., Gomes da Silva, M. M., Musungaie, D. B., Kovalchuk, E., Gonzalez, A., Delos Reyes, V., Martín-Quirós, A., Caraco, Y., Williams-Diaz, A., Brown, M. L., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2116044 · Cited by 1,857
A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
Boulware, D. R., Pullen, M. F., Bangdiwala, A. S., Pastick, K. A., Lofgren, S. M., Okafor, E. C., Skipper, C. P., Nascene, A. A., Nicol, M. R., Abassi, M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2016638 · Cited by 1,349
Self-citationCariou, B., Hadjadj, S., Wargny, M., Pichelin, M., Al‐Salameh, A., Allix, I., Amadou, C., Arnault, G., Baudoux, F., Bauduceau, B., et al. (2020) · Diabetologia · doi:10.1007/s00125-020-05180-x · Cited by 834
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
Skipper, C. P., Pastick, K. A., Engen, N. W., Bangdiwala, A. S., Abassi, M., Lofgren, S. M., Williams, D. A., Okafor, E. C., Pullen, M. F., Nicol, M. R., et al. (2020) · Annals of Internal Medicine · doi:10.7326/m20-4207 · Cited by 538
Self-citationLenze, E. J., Mattar, C., Zorumski, C. F., Stevens, A., Schweiger, J., Nicol, G. E., Miller, J. P., Yang, L., Yingling, M., Avidan, M. S., et al. (2020) · JAMA · doi:10.1001/jama.2020.22760 · Cited by 495
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Bramante, C. T., Buse, J. B., Liebovitz, D., Nicklas, J. M., Puskarich, M. A., Cohen, K., Belani, H., Anderson, B., Huling, J. D., Tignanelli, C. J., et al. (2023) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(23)00299-2 · Cited by 230
Self-citationLightner, A. L., Sengupta, V., Qian, S., Ransom, J. T., Suzuki, S., Park, D. J., Melson, T. I., Williams, B. P., Walsh, J. J., & Awili, M. (2023) · CHEST Journal · doi:10.1016/j.chest.2023.06.024 · Cited by 166
Signaling pathways in macrophages: molecular mechanisms and therapeutic targets
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Metadata
- 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
- 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
- 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 › Clinical 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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