A phase 3 randomized, controlled trial published today in the New England Journal of Medicine shows that three drugs repurposed for the treatment of COVID-19—metformin, ivermectin, and fluvoxamine—didn't prevent hypoxemia, an emergency department (ED) visit, hospitalization, or infection-related death, although a secondary analysis finds that metformin may hold some promise.
The double-blind COVID-OUT Trial Team, led by University of Minnesota researchers, evaluated the outcomes of 1,323 overweight or obese (body mass index [BMI], 25 kilograms per meter squared or greater) adult COVID-19 outpatients enrolled within 3 days of diagnosis and less than 7 days after symptom onset.
Median patient age was 46 years, 56% were women (6% of whom were pregnant), and 52.2% had been vaccinated against COVID-19. Patients were recruited from six US healthcare systems in Minnesota, Illinois, California, Colorado, and Indiana and enrolled from Dec 30, 2020, to Jan 28, 2022, with follow-up to Feb 14.
Metformin is a drug used to treat diabetes, ivermectin is used to treat parasite infestations, and fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used as therapy for obsessive-compulsive disorder and other conditions, such as depression.
Patients were randomly assigned to one of six groups to receive one of the three drugs individually, a combination of either metformin and fluvoxamine or metformin and ivermectin, or a placebo. Participants received two types of pills for 3 to 14 days to keep them from knowing which treatment they were receiving. They documented their symptoms each day and completed a survey after treatment ended.
Secondary analysis shows promise but isn't definitive
Hypoxemia, ED visit, hospitalization, or death occurred in 333 of 1,305 patients with complete data (25.5%). Through day 28, hospitalization or death occurred in 8 of 596 metformin patients (1.3%) and in 19 of 601 controls (3.2%). A total of 134 of 686 (19.5%) were vaccinated, and 199 of 615 (32.4%) were unvaccinated.
The adjusted odds ratio (aOR) for hypoxemia (oxygen saturation of 93% or less on a home oxygen monitor), ED visit, hospitalization, or death was 0.84 (95% confidence interval [CI], 0.66 to 1.09) with metformin, 1.05 (95% CI, 0.76 to 1.45) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36) with fluvoxamine.
A secondary analysis showed an aOR for an ED visit, hospitalization, or death of 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The aOR for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. The fluvoxamine arm was stopped early due to futility. The secondary analysis isn't conclusive because the group couldn't test its significance.
The results were comparable across subgroups, including vaccination status, dominant circulating SARS-CoV-2 variant, and pregnancy status. No general or COVID-specific symptoms resolved faster with placebo than with any trial drug, and no drug-related serious adverse events were reported.
Principal investigator and lead author Carolyn Bramante, MD, MPH, assistant professor of internal medicine and pediatrics at the University of Minnesota Medical School, told CIDRAP News that it's uncertain whether the results would generalize to adults whose BMI falls into the normal category. But because roughly 80% of American adults are overweight or obese, she said, they likely would generalize to most people, but the findings should be confirmed.
"All clinical trials should be evaluated critically, whether the primary outcome is positive or not and whether the secondary outcome is positive or not," she said.
Bramante said that metformin warrants further study. "I think metformin absolutely does," she said. "We really want others to replicate our findings in another trial or see if they aren't replicated. As far as fluvoxamine and ivermectin, the scientific community is probably going to be forming opinions in the coming weeks after they see our data."
The study authors noted that COVID-OUT was the first US trial to test the three medications and combinations thereof to prevent ED visits, hospitalization, or long COVID.
"A possible benefit for the prevention of the more severe components of the primary end point (emergency department visit, hospitalization, or death) was shown for metformin," they wrote. "However, this finding was a prespecified secondary end point and thus cannot be considered to be definitive pending the results of other trials."
"Although we know 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," Bramante said in a university news release.
"So we felt we should study safe, available and inexpensive outpatient treatment options as soon as possible," she said. "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."
Harms of using drugs that don't work
In a related commentary, Salim Abdool Karim, MB, ChB, PhD, of the Centre for the AIDS Programme of Research in South Africa, and Nikita Devnarian, PhD, of Columbia University in New York, said that prescribing medications that are known to be ineffective "is not a neutral or harmless option. In addition to denying patients the appropriate treatment, such prescribing can lead to side effects without any therapeutic benefit and to drug shortages for patients who need the medications for other conditions."
That's why, they said, it's important to have reliable evidence that certain drugs don't work against their intended target.
"As the American Board of Internal Medicine pointed out regarding the promotion of misinformation by physicians, 'There aren't always right answers, but some answers are clearly wrong,' " Karim and Devnarian wrote.
"With respect to clinical decisions about Covid-19 treatment, some drug choices, especially those that have negative WHO [World Health Organization] recommendations, are clearly wrong," they concluded. "In keeping with evidence-based medical practice, patients with Covid-19 must be treated with efficacious medications; they deserve nothing less."
