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Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial

42 Pages Posted: 6 Mar 2023

See all articles by Carolyn Bramante

Carolyn Bramante

University of Minnesota - Minneapolis - General Internal Medicine

John B. Buse

University of North Carolina at Chapel Hill - Endocrinology

David Liebovitz

Northwestern University - Division of General Internal Medicine

Jacinda Nicklas

University of Colorado at Denver - General Internal Medicine

Michael Puskarich

Hennepin County Medical Center - Emergency Medicine

Kenneth R. Cohen

UnitedHealth Group - Optum Labs

Hrishikesh Belani

University of California, Los Angeles (UCLA) - Department of Medicine, Olive View

Blake Anderson

Atlanta Veterans Affairs Medical Center; Emory University - Department of Medicine

Jared D. Huling

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

Christopher Tignanelli

University of Minnesota - Minneapolis - Institute for Health Informatics; University of Minnesota - Minneapolis - Department of Surgery; North Memorial Health Hospital - Department of Surgery

Jennifer Thompson

Vanderbilt University - Department of Obstetrics and Gynecology

Matthew Pullen

University of Minnesota - Minneapolis - Infectious Diseases

Esteban Lemus Wirtz

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

Lianne Siegel

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

Jennifer Proper

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

David J. Odde

University of Minnesota - Department of Biomedical Engineering

Nichole Klatt

University of Minnesota - Minneapolis - Department of Surgery, Medical School

Nancy E. Sherwood

University of Minnesota - Minneapolis - Division of Epidemiology and Community Health

Sarah Lindberg

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

Amy B. Karger

University of Minnesota - Minneapolis - Department of Laboratory Medicine and Pathology

Kenneth B. Beckman

University of Minnesota - Minneapolis - University of Minnesota Genomics Center

Spencer Erickson

University of Minnesota - Minneapolis - General Internal Medicine

Sarah Fenno

University of Minnesota - Minneapolis - General Internal Medicine

Katrina Hartman

University of Minnesota - Minneapolis - General Internal Medicine

Michael Rose

Johns Hopkins University - Department of Medicine

Tanvi Mehta

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health

Barkha Patel

University of Minnesota - Minneapolis - General Internal Medicine

Gwendolyn Griffiths

University of Minnesota - Minneapolis - General Internal Medicine

Neeta Bhat

University of Minnesota - Minneapolis - General Internal Medicine

Thomas A. Murray

University of Minnesota - Minneapolis - Division of Biostatistics

David R. Boulware

Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota

More...

Abstract

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID. 

Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2x3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records. 

Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed >9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34). Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95%CI, 0.38 to 0.88; P=0·009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within <4 days of symptom onset, the HR for Long COVID was 0.37 (95%CI, 0.15 to 0.95).  No statistical difference in Long COVID occurred in those randomized to either ivermectin (HR=0.99; 95%CI, 0.59 to 1.64) or fluvoxamine (HR=1.36; 95%CI, 0.78 to 2.34).

Interpretations: A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.

Trial Registration: ClinicalTrials.gov: NCT04510194.

Funding: The trial was funded by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation.

Declaration of Interest: 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.

Ethical Approval: Institutional review boards at each site, and Advarra centrally, approved the protocol. An independent data safety monitoring board (DSMB) oversaw safety and efficacy monitoring, and an independent monitor oversaw study conduct in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and local requirements.

Keywords: Long COVID, COVID, Metformin, Randomized Clinical Trial

Suggested Citation

Bramante, Carolyn and Buse, John B. and Liebovitz, David and Nicklas, Jacinda and Puskarich, Michael and Cohen, Kenneth R. and Belani, Hrishikesh and Anderson, Blake and Huling, Jared D. and Tignanelli, Christopher and Thompson, Jennifer and Pullen, Matthew and Wirtz, Esteban Lemus and Siegel, Lianne and Proper, Jennifer and Odde, David J. and Klatt, Nichole and Sherwood, Nancy E. and Lindberg, Sarah and Karger, Amy B. and Beckman, Kenneth B. and Erickson, Spencer and Fenno, Sarah and Hartman, Katrina and Rose, Michael and Mehta, Tanvi and Patel, Barkha and Griffiths, Gwendolyn and Bhat, Neeta and Murray, Thomas A. and Boulware, David R., Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial. Available at SSRN: https://ssrn.com/abstract=4375620 or http://dx.doi.org/10.2139/ssrn.4375620

Carolyn Bramante (Contact Author)

University of Minnesota - Minneapolis - General Internal Medicine

John B. Buse

University of North Carolina at Chapel Hill - Endocrinology ( email )

David Liebovitz

Northwestern University - Division of General Internal Medicine ( email )

Jacinda Nicklas

University of Colorado at Denver - General Internal Medicine ( email )

Michael Puskarich

Hennepin County Medical Center - Emergency Medicine ( email )

Kenneth R. Cohen

UnitedHealth Group - Optum Labs ( email )

Hrishikesh Belani

University of California, Los Angeles (UCLA) - Department of Medicine, Olive View ( email )

Blake Anderson

Atlanta Veterans Affairs Medical Center ( email )

Emory University - Department of Medicine ( email )

Atlanta, GA
United States

Jared D. Huling

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

Christopher Tignanelli

University of Minnesota - Minneapolis - Institute for Health Informatics

Minneapolis, MN
United States

University of Minnesota - Minneapolis - Department of Surgery ( email )

420 Delaware St. SE
Minneapolis, MN 55455
United States
(612) 625-7911 (Phone)

North Memorial Health Hospital - Department of Surgery

Robbinsdale, MN
United States

Jennifer Thompson

Vanderbilt University - Department of Obstetrics and Gynecology ( email )

Matthew Pullen

University of Minnesota - Minneapolis - Infectious Diseases ( email )

Esteban Lemus Wirtz

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

Lianne Siegel

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

Jennifer Proper

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

David J. Odde

University of Minnesota - Department of Biomedical Engineering ( email )

Minneapolis, MN 55455
United States

Nichole Klatt

University of Minnesota - Minneapolis - Department of Surgery, Medical School ( email )

Nancy E. Sherwood

University of Minnesota - Minneapolis - Division of Epidemiology and Community Health ( email )

Sarah Lindberg

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

Amy B. Karger

University of Minnesota - Minneapolis - Department of Laboratory Medicine and Pathology ( email )

Minneapolis, MN
United States

Kenneth B. Beckman

University of Minnesota - Minneapolis - University of Minnesota Genomics Center ( email )

Spencer Erickson

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Sarah Fenno

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Katrina Hartman

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Michael Rose

Johns Hopkins University - Department of Medicine ( email )

Tanvi Mehta

University of Minnesota - Minneapolis - Division of Biostatistics, School of Public Health ( email )

Barkha Patel

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Gwendolyn Griffiths

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Neeta Bhat

University of Minnesota - Minneapolis - General Internal Medicine ( email )

Thomas A. Murray

University of Minnesota - Minneapolis - Division of Biostatistics ( email )

David R. Boulware

Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota ( email )

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