No win for metformin, ivermectin, fluvoxamine in preventing severe COVID-19

The use of metformin, fluvoxamine, or ivermectin in an outpatient setting did not appear to prevent progression to severe COVID-19, according to results of the phase III COVID-OUT trial.  

“[N]one of the three drugs had a significant effect on the composite primary end point of hypoxaemia, emergency department (ED) visit, hospitalization, or death,” said the investigators.

“[However,] our trial suggests that metformin may reduce the likelihood of needing to go to the emergency room or be hospitalized for COVID-19,” noted principal investigator Assistant Professor Carolyn Bramante from the University of Minnesota, Minneapolis, Minnesota, US.

Study participants were 1,323 non-hospitalized patients aged 30–85 years (median age 46 years, 56 percent female [6.1 percent of whom were pregnant]) with confirmed SARS-CoV-2 infection ≤3 days prior who were overweight or obese (median BMI 30 kg/m²). Within 7 days of symptom onset (mean 4.8 days), they were randomized, double-blind to one of six groups (group 1: metformin* + fluvoxamine*; group 2: metformin + ivermectin*; group 3: metformin + placebo; group 4: placebo + fluvoxamine; group 5: placebo + ivermectin; or group 6: placebo + placebo). Fifty-two percent of the population had received COVID-19 vaccination.

At 14 days, none of the medications improved the primary outcome which was a composite of hypoxaemia (≤93 percent oxygen saturation on home oximetry), ED visit, hospitalization, or death (metformin**: 23.6 percent vs 27.4 percent [control]; adjusted odds ratio [adjOR], 0.84, 95 percent confidence interval [CI], 0.66–1.09; p=0.19; ivermectin**: 25.8 percent vs 24.6 percent; adjOR, 1.05, 95 percent CI, 0.76–1.45; p=0.78; fluvoxamine: 24.0 percent vs 24.9 percent; adjOR, 0.94, 95 percent CI, 0.66–1.36; p=0.75). [N Engl J Med 2022;387:599-610]

There was a trend toward a reduced risk of the prespecified secondary composite outcome of ED visit, hospitalization, or death among patients assigned to metformin (4.1 percent vs 7.3 percent [control]; adjOR, 0.58, 95 percent CI, 0.35–0.94), but not among those assigned to ivermectin (5.7 percent vs 4.1 percent; adjOR, 1.39, 95 percent CI, 0.72–2.69), or fluvoxamine (5.5 percent vs 4.6 percent; adjOR, 1.17, 95 percent CI, 0.57–2.40).

The outcome of hospitalization or death was not significantly reduced in any of the treatment arms (metformin: 1.2 percent vs 2.7 percent; adjOR, 0.47, 95 percent CI, 0.20–1.11; ivermectin: 1.0 percent vs 1.3 percent; adjOR, 0.73, 95 percent CI, 0.19–2.77; fluvoxamine: 1.8 percent vs 1.5 percent; adjOR, 1.11, 95 percent CI, 0.33–3.76). There was one death each in the metformin and ivermectin arms.

“None of the trial drugs resulted in a lower severity of symptoms than identically matched placebo,” the investigators said.

Why the need for more meds?

“Although … COVID-19 vaccines are highly effective, we know that some new strains of the virus may evade immunity and vaccines may not be available worldwide. So we felt we should study safe, available, and inexpensive outpatient treatment options as soon as possible,” said Bramante. “Understanding whether outpatient treatments could ensure more people survive the illness if they contract it and have fewer long-term symptoms is an important piece of the pandemic response.”

The positive finding with regard to metformin “cannot be considered definitive” seeing as how it is a secondary endpoint, noted the investigators. Additionally, a higher dose of fluvoxamine may produce different results, particularly in an overweight or obese population, they said.

“[Nonetheless,] we are pleased to contribute to the body of knowledge around COVID-19 therapies in general, with treatments that are widely available,” said Bramante.

Study limitations included restricting the population to overweight or obese individuals in the US and the inclusion of home-measured hypoxaemia in the primary endpoint which may be subject to inaccuracy.