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All Studies   Meta Analysis       

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

Bramante et al., NEJM, doi:10.1056/NEJMoa2201662, COVID-OUT, NCT04510194
Aug 2022  
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Death/hospitalization -11% Improvement Relative Risk Progression, ER, hosp., de.. -16% Hospitalization, day 28 2% Hospitalization, day 14 2% Progression, hypoxemia.. 5% primary Fluvoxamine  COVID-OUT  EARLY TREATMENT  DB RCT Is early treatment with fluvoxamine beneficial for COVID-19? Double-blind RCT 653 patients in the USA Control group includes metformin patients No significant difference in outcomes seen c19early.org Bramante et al., NEJM, August 2022 Favorsfluvoxamine Favorscontrol (inc.. 0 0.5 1 1.5 2+
27th treatment shown to reduce risk in November 2021, now with p = 0.00014 from 21 studies, recognized in 3 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 109 treatments. c19early.org
COVID-OUT remotely operated RCT, showing no significant difference in outcomes. Results for other treatments are listed separately - metformin, ivermectin.
The "control" group includes patients receiving metformin, which is known to be beneficial for COVID-191.
Authors note that the dosage used in the trial is lower than that of other trials2.
Control arm results are very different between treatments, for example considering hospitalization/death, this was 1.0% for ivermectin vs. 2.7% for overall control, however it was 1.3% for the ivermectin-specific control. 394 control patients are shared. The rate for the non-shared 261 metformin control patients is 5%, compared to 1.3% for ivermectin control patients. The metformin arm started earlier, however it is unclear why the difference in outcomes is so large.
Results were delayed for 6 months with no explanation, with followup ending Feb 14, 2022.
Multiple outcomes are missing, for example time to recovery (where ACTIV-6 showed superiority of ivermectin).
Adherence was very low, with 77% overall reporting 70+% adherence. Numbers for 100% adherence are not provided.
Treatment was 14 days for metformin and fluvoxamine, but only 3 days for ivermectin.
Trial outcomes were changed on January 20, 20223, and again on March 2, 20224. COVIDOUT.
Medication delivery varied significantly over the trial. In this presentation5, author indicates that delivery was initially local, later via FedEx, was much slower in August, there were delays due to team bandwidth issues, and they only realized they could use FedEx same day delivery in September.
Study covers ivermectin, fluvoxamine, and metformin.
risk of death/hospitalization, 10.8% higher, RR 1.11, p = 0.88, treatment 6 of 329 (1.8%), control 5 of 324 (1.5%), odds ratio converted to relative risk.
risk of progression, 16.1% higher, RR 1.16, p = 0.68, treatment 18 of 329 (5.5%), control 15 of 324 (4.6%), odds ratio converted to relative risk, combined ER, hospitalization, death.
risk of hospitalization, 1.5% lower, RR 0.98, p = 1.00, treatment 5 of 329 (1.5%), control 5 of 324 (1.5%), NNT 4264, Figure S8, day 28.
risk of hospitalization, 1.5% lower, RR 0.98, p = 1.00, treatment 5 of 329 (1.5%), control 5 of 324 (1.5%), NNT 4264, Figure S7, day 14.
risk of progression, 4.6% lower, RR 0.95, p = 0.75, treatment 79 of 329 (24.0%), control 80 of 321 (24.9%), NNT 110, odds ratio converted to relative risk, combined hypoxemia, ER, hospitalization, death, primary outcome.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Bramante et al., 18 Aug 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 37 authors, average treatment delay 5.0 days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04510194 (history) (COVID-OUT).
This PaperFluvoxamineAll
Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19
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
New England Journal of Medicine, doi:10.1056/nejmoa2201662
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.
Appendix The authors' full names and academic degrees are as follows: Carolyn T. Bramante
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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...'}]}, { 'ORCID': 'http://orcid.org/0000-0001-6723-0423', 'authenticated-orcid': False, 'given': 'Katrina M.', 'family': 'Hartman', 'sequence': 'additional', 'affiliation': [ { 'name': '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...'}]}, { 'given': 'Via', 'family': 'Rao', 'sequence': 'additional', 'affiliation': [ { 'name': '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...'}]}, { 'given': 'Aubrey A.', 'family': 'Hagen', 'sequence': 'additional', 'affiliation': [ { 'name': '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. 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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...'}]}, { 'given': 'Nandini', 'family': 'Avula', 'sequence': 'additional', 'affiliation': [ { 'name': '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. 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