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

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