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Three Repurposed Drugs Flop for Thwarting Severe COVID

— High-risk patients saw no benefits from metformin, ivermectin, or fluvoxamine

Last Updated August 23, 2022
MedpageToday
Boxes of Metformin and Ivermectin tablets and a bottle of Fluvoxamine tablets over a computer rendering of covid viruses.

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

Among over 1,300 patients with overweight or obesity, 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 .

In prespecified secondary analyses, the adjusted odds ratios for an ED visit/hospitalization/death and hospitalization/death with 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 the prevention of the more severe components of the primary endpoint ... was shown for metformin ... this finding was a prespecified secondary endpoint and thus cannot be considered to be definitive pending the results of other trials," Bramante and team wrote.

"Metformin had several streams of evidence supporting its use -- in vitro, in silico, observational, and in tissue," Bramante told 鶹ý.

Given that the primary outcome was negative but the secondary outcome positive, "a confirmatory trial for metformin is particularly important," she added.

In an , Salim S. Abdool Karim, MB, ChB, PhD, and Nikita Devnarain, PhD, of the Mailman School of Public Health at Columbia University in New York City, noted that doctors are doing more harm than good by using drugs that don't work, asking, "How much evidence of nonefficacy is enough?"

"Prescribing nonefficacious treatments is not a neutral or harmless option," they wrote, pointing out that not only does this practice keep patients from getting the right treatment, it also can lead to potential side effects and drug shortages for patients who need the drugs for other illnesses.

"Hence, it is important to have reliable evidence of nonefficacy and to have journals publish such studies," they continued. "It is also important that multiple rigorous randomized, controlled trials be performed to provide unequivocal evidence on the efficacy of new treatments."

"In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less," they concluded.

For this double-blind, placebo-controlled study, which was conducted from Dec. 30, 2020 to Jan. 28, 2022, Bramante and colleagues included 1,323 patients (median age 46, 56% women) from six institutions. Six percent of the women were pregnant, and 52.2% of the overall group were vaccinated.

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

The participants were assigned to the three drugs using a 2-by-3 factorial design: 663 were assigned to metformin and were compared to 660 in the placebo group; 410 were assigned to ivermectin and were compared to 398 placebo patients; and 334 were assigned to fluvoxamine and were compared to 327 in the placebo group.

All patients had to be enrolled within 3 days of a confirmed COVID diagnosis and less than 7 days after onset of symptoms.

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

Bramante and colleagues acknowledged that their findings may not be generalizable to those without overweight or obesity.

  • author['full_name']

    Ingrid Hein is a staff writer for 鶹ý covering infectious disease. She has been a medical reporter for more than a decade.

Disclosures

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

Bramante and co-authors 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 the Institute for Engineering in Medicine, the Medtronic Professorship for Engineering in Medicine, and the Medtronic Faculty Fellowship.

Karim reported being a member of the WHO Science Council. Devnarain had no disclosures.

Primary Source

New England Journal of Medicine

Bramante CT, et al "Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19" N Engl J Med 2022; DOI: 10.1056/NEJMoa2201662.

Secondary Source

New England Journal of Medicine

Abdool Karim SS, Devnarain N "Time to stop using ineffective Covid-19 drugs" N Engl J Med 2022; DOI: 10.1056/NEJMe2209017.