Metformin, Ivermectin, and Fluvoxamine Do Not Prevent Severe COVID-19 Outcomes

Metformin, ivermectin, or fluvoxamine does not prevent severe COVID-19 among nonhospitalized adults who are classified as overweight or obese.

Treatment with metformin, ivermectin, or fluvoxamine for COVID-19 among nonhospitalized adults did not lead to any observed benefits compared with placebo, according to study findings published in The New England Journal of Medicine.

As protection from vaccination against SARS-CoV-2 wanes among the general population, effective outpatient therapies to decrease risk for severe disease are needed.

This phase 3, double-blind, randomized, placebo-controlled trial (COVID-OUT; Identifier: NCT04510194) was conducted at 6 centers in the United States between December 2020 and January 2022. Adults (N=1431) who were classified as overweight or obese with onset of COVID-19 symptoms within 7 days were randomized to receive the following:

  • Metformin plus fluvoxamine
  • Metformin plus ivermectin
  • Metformin plus placebo
  • Placebo plus fluvoxamine
  • Placebo plus ivermectin
  • Placebo plus placebo

The dosing for metformin was increased over 6 days to 15 mg for 14 days, ivermectin was given as 390-470 μg/kg for 3 days, and fluvoxamine as 50 mg twice a day for 14 days. The primary endpoint was the composite rates of severe COVID-19, defined as ≤93% oxygen saturation on home oximetry, emergency department (ED) visit, hospitalization, and death.

The study cohorts included patients aged median 43-46 years, 50.9%-57.9% were women, 80.9%-82.9% were White, 46.4%-50.0% had a body mass index (BMI) of 30 kg/m2 or higher, and 65.3%-84.1% were infected with the Delta variant.

None of the trial drugs resulted in a lower severity of symptoms than identically matched placebo.

Among patients with complete data (n=1305), the primary composite outcome of severe disease, mortality, ED visit, or hospitalization occurred among 25.5%. More of the patients who did not reach the primary endpoint were vaccinated (32.4%) compared with those who met the composite endpoint (19.5%).

Metformin (adjusted odds ratio [aOR], 0.84; 95% CI, 0.66-1.09; P =.19), ivermectin (aOR, 1.05; 95% CI, 0.76-1.45; P =.78), and fluvoxamine (aOR, 0.94; 95% CI, 0.66-1.36; P =.75) were not associated with decreased risk for the primary outcome compared with placebo. Similarly, no study interventions associated with a significant effect for reducing risk for hypoxemia, ED visits, hospitalization, or death compared with placebo.

In addition, patients were asked to record the symptoms they were experiencing every day for 14 days. No evidence supported a faster recovery from symptoms compared with placebo for any intervention.

This study may have been limited by only recruiting patients aged 30-85 years who were identified as overweight or obese, and these findings may not be generalizable.

These data do not support the use of metformin, ivermectin, or fluvoxamine as an outpatient intervention to decrease risk for severe COVID-19 disease among adults who were classified as overweight or obese.

The researchers concluded that “None of the trial drugs resulted in a lower severity of symptoms than identically matched placebo.”


Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med. August 18, 2022. doi:10.1056/NEJMoa2201662