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 2×3 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.
Source: 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 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