Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19
COVID-OUT remotely operated RCT,
showing no significant difference in outcomes. Results for other treatments
are listed separately -
The "control" group includes patients receiving metformin,
which is known to be beneficial for COVID-19
Authors note that the dosage used in the trial is lower than
that of other trials
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.
Medication delivery varied significantly over the trial. In
this presentation [vimeo.com]
, 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.
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, 3 authors, average treatment delay 5.0 days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04510194 (history)
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
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
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.
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
email@example.com 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.
Copyright © 2022 Massachusetts Medical Society.
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)
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
August 18, 2022
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