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0 0.5 1 1.5 2+ PASC 41% Improvement Relative Risk PASC (b) 1% unadjusted PASC (c) -36% unadjusted Metformin  Bramante et al.  EARLY TREATMENT  RCT Is early treatment with metformin beneficial for COVID-19? RCT in the USA Lower PASC with metformin (p=0.013) Bramante et al., The Lancet Infectious.., Dec 2022 Favors metformin Favors control

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial

Bramante et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(23)00299-2, NCT04510194
Dec 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 87 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Long-term 10 month followup for NCT04510194 (history), showing significantly lower incidence of PASC with metformin treatment. Adjusted results are provided for metformin but not for ivermectin or fluvoxamine. For many issues with this trial, see Bramante.
risk of PASC, 41.2% lower, HR 0.59, p = 0.01, adjusted per study, metformin.
risk of PASC, 1.4% lower, HR 0.99, p = 0.96, unadjusted, ivermectin.
risk of PASC, 36.0% higher, HR 1.36, p = 0.28, unadjusted, fluvoxamine.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Bramante et al., 24 Dec 2022, Randomized Controlled Trial, USA, peer-reviewed, median age 45.0, 31 authors, trial NCT04510194 (history). Contact:
This PaperMetforminAll
Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up
MD, MPH Carolyn T Bramante, MD, PhD John B Buse, MD David Liebovitz, MD, MPH Jacinda Nicklas, MD Michael A Puskarich, MD Ken Cohen, MD Hrishikesh Belani, MS Blake Anderson, PhD Jared D Huling, MD, MS Christopher Tignanelli, MD, MPH Jennifer Thompson, MD Matthew Pullen, PhD Lianne Siegel, PhD Jennifer Proper, PhD David J Odde, PhD Nichole Klatt, PhD Nancy Sherwood, MPH Sarah Lindberg, Esteban Lemus Wirtz, MD, PhD Amy Karger, PhD Kenny Beckman, BA Spencer Erickson, MPH Sarah Fenno, BA Katrina Hartman, MD Michael Rose, MS Barkha Patel, BA Gwendolyn Griffiths, MPH Neeta Bhat, PhD Thomas A Murray, MD, MPH David R Boulware
Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigatorinitiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m 2 (IQR 27 to 34); 51% had a BMI >30kg/m 2 . Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.
Disclosures JBB reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by Dexcom, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc, Boehringer-Ingelheim, CeQur, Cirius Therapeutics Inc, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns Inc, Valo and Zealand Pharma; and stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health.
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