Highlights
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Background :
Post-acute COVID, called “long COVID ,” is an emerging chronic disease that may affect ~10% of people with COVID-19. We sought to determine whether 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 that tested three medications ( metformin, ivermectin, fluvoxamine ) using 2x3 parallel treatment factorial randomization to efficiently share placebo controls. Participants, investigators, care providers, and outcome assessors were blinded to random treatment assignment.
Inclusion criteria included : age 30-85 years overweight or obese, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a prespecified secondary outcome assessed by monthly surveys for 300 days after randomization and confirmed in medical records.
Findings:
Of 1,323 randomized trial participants, 1,125 consented to long-term follow-up and 95.1% completed more than 9 months of follow-up.
- The median age was 45 years (IQR, 37 to 54), and 56% were women (7% pregnant).
- Median BMI was 30 kg/m2 (IQR, 27 to 34).
- Overall, 8.4% reported being diagnosed with long COVID by a medical provider; 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 effect of metformin was consistent across all subgroups, including viral variants. When metformin was initiated within <4 days of symptom onset, the HR for Long COVID was 0.37 (95% CI, 0.15 to 0.95).
There was no statistical difference in Long COVID in those randomized to ivermectin (HR = 0.99; 95% CI, 0.59 to 1.
Interpretations:
There was a 42% relative decrease and a 4.3% absolute decrease in the incidence of long-term COVID-19 in participants who received early outpatient metformin treatment for COVID-19 compared to exact-match placebo.
Discussion
COVID-OUT was a phase 3, randomized, quadruple-blind, placebo-controlled, investigator-initiated, multi-site, outpatient Covid-19 treatment clinical trial that followed 288 participants for 10 months to evaluate whether early treatment prevented the development of long COVID.
Metformin treatment during acute Covid-19 infection prevented more than 40% of long Covid cases , with 6.3% of participants in the metformin group and 10.6% in the placebo group receiving a Long Covid diagnosis from a medical provider.
Conclusions
Outpatient treatment with metformin at the time of SARS-CoV-2 infection decreased the development of Long Covid by 42% in a randomized phase 3 trial, and by more than 50% when initiated less than 4 days from infection. onset of symptoms. This finding is consistent with the 42% reduction in healthcare utilization for severe Covid-19 with metformin in the first 14 days of the trial.
Fluvoxamine and ivermectin did not reduce the development of long Covid, which is consistent with the results in the first 14 days of the trial.
These results are highly relevant to the current state of the pandemic because approximately half of the study sample was vaccinated and, despite the 10-month follow-up of these results, the trial was enrolled during the Omicron wave. Long Covid is a major public health emergency that can have lasting health, mental health and economic consequences, especially in socioeconomically marginalized groups, and metformin is safe, low-cost and widely available.
