Boxes of Metformin and Ivermectin tablets and a bottle of Fluvoxamine tablets over a computer rendering of covid viruses.

Failure of three drugs repurposed to thwart severe COVID

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Early treatment with three repurposed drugs (metformin, ivermectin, or fluvoxamine) did not prevent severe COVID-19 outcomes in high-risk patients, according to a phase III randomized trial.

Among more than 1,300 overweight or obese patients, the adjusted odds ratio for a primary event, including hypoxemia, an emergency department (ED) visit, hospitalization, or death, was 0.84 (95% CI : 0.66-1.09, P=0.19) with metformin, 1.05 (95% CI 0.76-1.45, P=0.78) with ivermectin, and 0.94 (95% CI 0.66-1.36, P=0.75) with fluvoxamine, compared with placebo, reported Carolyn T. Bramante, MD, MPH, of the University of Minnesota in Minneapolis, and colleagues in the New England Journal of Medicine.

In prespecified secondary analyses, the adjusted odds ratios for ED visit/hospitalization/death and hospitalization/death for the three drugs were:

  • 0.58 (95% CI 0.35-0.94) and 0.47 (95% CI 0.20-1.11) with metformin
  • 1.39 (95% CI 0.72-2.69) and 0.73 (95% CI 0.19-2.77) with ivermectin
  • 1.17 (95% CI 0.57-2.40) and 1.11 (95% CI 0.33-3.76) with fluvoxamine

While a “possible benefit for prevention of the most serious components of the primary endpoint … was demonstrated for metformin … this finding was a prespecified secondary endpoint and therefore cannot be considered definitive at pending the results of other trials. Bramante and his team wrote.

In an accompanying editorial, Salim S. Abdool Karim, MB, ChB, PhD, and Nikita Devnarain, PhD, of Columbia University’s Mailman School of Public Health in New York City, point out that doctors are doing more harm than good at using drugs that don’t work, asking, “How much evidence of ineffectiveness is enough?”

“Prescribing ineffective treatments is not a neutral or harmless option,” they wrote, noting that this practice not only prevents patients from receiving the appropriate treatment, but can also lead to potential side effects and drug shortages for patients who need the drugs. medicines for other diseases

“Therefore, it is important to have reliable evidence of lack of efficacy and for journals to publish such studies,” they continued. “It is also important that multiple rigorous randomized controlled trials be conducted to provide unequivocal evidence on the efficacy of new treatments.”

“According to evidence-based medical practice, COVID-19 patients should be treated with effective medications, they deserve no less,” they concluded.

For this double-blind, placebo-controlled study, which was conducted from December 30, 2020, to January 28, 2022, Bramante and colleagues enrolled 1,323 patients (mean age 46, 56% female) from six institutions. Six percent of the women were pregnant and 52.2% of the total group were vaccinated.

The primary composite endpoint was hypoxemia (≤93% oxygen saturation on home oximetry), one emergency department visit, hospitalization, or death.

Participants were assigned to the three medications using a 2 by 3 factorial design: 663 were assigned to metformin and compared with 660 in the placebo group; 410 were assigned to ivermectin and compared with 398 patients on placebo; and 334 were assigned to fluvoxamine and compared with 327 in the placebo group.

All patients were required to enroll within 3 days of a confirmed COVID diagnosis and less than 7 days after symptom onset.

Of the 1,305 patients with complete data, 25.5% had a primary event, of whom 19.5% were vaccinated.

Bramante and his colleagues acknowledged that their findings may not generalize to people who are not overweight or obese.


This study was supported by the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation. Fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. Ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals.

Bramante and coauthors were supported by grants from the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the National Cancer Institute, as well as such as the Institute for Medical Engineering, the Medtronic Chair for Medical Engineering, and the Medtronic Faculty Scholarship.

Karim reported being a member of the WHO Scientific Council. Devnarain made no disclosures.

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