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0 0.5 1 1.5 2+ Mortality, day 28 3% Improvement Relative Risk Mortality, day 14 -197% Death/hospitalization 52% Progression 40% Progression (b) 12% primary Viral clearance, day 10 37% Viral clearance, day 5 9% Metformin  COVID-OUT  EARLY TREATMENT  DB RCT Is early treatment with metformin beneficial for COVID-19? Double-blind RCT 1,307 patients in the USA Trial compares with control (including fluvoxamine and ivermectin) Lower progression (p=0.033) and improved viral clearance (p=0.00079) Bramante et al., NEJM, August 2022 Favors metformin Favors control (inc..

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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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
*, now known with p < 0.00000000001 from 84 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
COVID-OUT remotely operated RCT, showing lower combined ER/hospitalization/death with metformin. Results for other treatments are listed separately - ivermectin, fluvoxamine.
The "control" group includes patients receiving active treatments fluvoxamine and ivermectin.
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.
Adherence was very low, with 77% overall reporting 70+% adherence. Numbers for 100% adherence are not provided.
Multiple outcomes are missing, for example time to recovery (where ACTIV-6 showed superiority of ivermectin).
Treatment was 14 days for metformin and fluvoxamine, but only 3 days for ivermectin.
Trial outcomes were changed on January 20, 2022, and again on March 2, 2022 (B). COVIDOUT.
Medication delivery varied significantly over the trial. In this presentation, 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, 2.9% lower, RR 0.97, p = 1.00, treatment 1 of 408 (0.2%), control 1 of 396 (0.3%), NNT 13464, day 28.
risk of death, 197.1% higher, RR 2.97, p = 1.00, treatment 1 of 408 (0.2%), control 0 of 396 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 14.
risk of death/hospitalization, 52.3% lower, RR 0.48, p = 0.09, treatment 8 of 652 (1.2%), control 18 of 655 (2.7%), NNT 66, odds ratio converted to relative risk.
risk of progression, 40.2% lower, RR 0.60, p = 0.03, treatment 27 of 652 (4.1%), control 48 of 655 (7.3%), NNT 31, odds ratio converted to relative risk, combined ER, hospitalization, death.
risk of progression, 12.1% lower, RR 0.88, p = 0.18, treatment 154 of 652 (23.6%), control 179 of 653 (27.4%), NNT 26, odds ratio converted to relative risk, combined hypoxemia, ER, hospitalization, death, primary outcome.
risk of no viral clearance, 36.9% lower, RR 0.63, p < 0.001, treatment 72 of 504 (14.3%), control 112 of 495 (22.6%), NNT 12, day 10.
risk of no viral clearance, 8.7% lower, RR 0.91, p = 0.15, treatment 251 of 504 (49.8%), control 270 of 495 (54.5%), NNT 21, day 5.
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 4.8 days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04510194 (history) (COVID-OUT).
This PaperMetforminAll
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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