Researchers examine metformin, ivermectin, and fluvoxamine for COVID-19 treatment

COVID-19 Meds

Corey Diamond, PharmD

As the COVID-19 pandemic surges on, the public has seen the rise and fall of several promising therapeutic agents for COVID-19 outpatient treatment. These agents include metformin, ivermectin, and fluvoxamine, which demonstrated potential benefits from in vitro studies and early randomized controlled trials.

However, a new study—the COVID-OUT trail—sought to definitively evaluate the efficacy of these 3 agents in a single maneuver. In the study, which was published August 18, 2022, in The New England Journal of Medicine, researchers reported no significant reductions in hypoxemia, emergency department visits, hospitalization, or mortality with any of the 3 drugs.

All-in-one design

In the study, Bramante and colleagues conducted a randomized controlled trial that evaluated the effects of metformin, ivermectin, and fluvoxamine on outpatients infected with COVID-19. The patients had an onset of symptoms within 7 days of randomization. The researchers were able to measure the effects of the 3 medications independently and simultaneously using a 2 × 3 factorial design. The study was conducted across 6 medical institutions in the United States and included data from over 1,300 patients. Notably, the median BMI of the trial participants was 30 and about half had received a COVID-19 vaccination.

In order to study the independent effects of all 3 medications at the same time, the researchers randomized the patients into 6 groups: Metformin plus fluvoxamine, metformin plus ivermectin, metformin plus placebo, placebo plus fluvoxamine, placebo plus ivermectin, and placebo plus placebo.

The COVID-OUT trial’s primary efficacy endpoint was severe COVID-19, which they defined as a composite of hypoxemia, emergency department visits, hospitalization, or death through 14 days after beginning treatment. Secondary endpoints of the analysis included the individual components of the primary endpoint. The researchers also assessed daily symptom severity and drug discontinuation frequency as secondary endpoints.

The researchers found a statistically insignificant difference in the odds ratios of the primary compositive endpoint for metformin, ivermectin, and fluvoxamine. This finding held true in a secondary analysis of a composite endpoint of just hospitalization or death, as well.

Additionally, no significant reductions in self-reported overall symptoms or COVID-19–related symptoms were observed between groups. The only notable finding detected in the analysis was a statistically significant 43% odds reduction in the secondary composite endpoint of emergency department visit, hospitalization, or death with metformin.

Rationale for design

The year 2020 saw a desperate scramble in the scientific community to identify pre-existing drugs that could be repurposed to target COVID-19. Metformin, for instance, was shown to have in vitro activity against COVID-19 and inhibitory actions on interleukins. Additionally, several observational studies from 2021 detected less severe COVID-19 in patients who had already been taking metformin prior to infection.

Early on in the pandemic, ivermectin demonstrated in vitro activity against COVID-19, but at concentrations impractical to achieve reliably in the human body.

Using ivermectin to treat COVID-19 has been extremely contentious. Its potential as a COVID-19 treatment option spurred the scientific community further due to an early preprint of a study by Elgazzar and colleagues in Research Square, which has since been withdrawn due to allegations of research fraud. However, questions have continued to resurface regarding ivermectin’s lack of data. For instance, the EPIC trial, published in JAMA in 2021, evaluated the use of ivermectin at 300 mcg/kg of bodyweight per day versus placebo. While the study found no effect on symptom resolution, the authors raised the possibility of a lack of effect due to subtherapeutic dosage. The COVID-OUT trial remedied this doubt by using a median dosage of 430 mcg/kg per day.

Finally, research has shown that fluvoxamine may have anti-inflammatory and antiprotein transfer effects on the COVID-19 virion assembly process, which are both mediated by the sigma-1 receptor.

Early randomized trials investigating 100 mg 2 to 3 times daily reported a 25–30% reduction in hospitalization.

However, the results of the COVID-OUT trial can only be extrapolated to a dose of 50 mg twice daily, and more studies will be needed to confirm the efficacy of the higher dosage.WHO recommendations for COVID-19 therapeutics

Implications

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” stated an editorial published August 18, 2022, in The New England Journal of Medicine.

The editorial authors continue by cautioning the prescribing of nonefficacious treatments, warning that they are 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.”

It could be said that the objective of the COVID-OUT trial was to provide a high-quality randomized trial to assess the true efficacy of all 3 of these agents in one fell swoop.

Resources

At this time, WHO’s Therapeutics and COVID-19: Living Guideline is one of the best ways for pharmacists to stay up to date on the latest evidence surrounding candidate medications for the treatment of COVID-19.

The guideline currently offers 19 recommendations, including ones for fluvoxamine and ivermectin.

While the resource does not currently incorporate data from the COVID-OUT trial, it is expected to do so in the coming months. The table includes a concise breakdown on the current
recommendations of COVID-19 candidate drugs based on WHO’s disease severity criteria.

The guideline may still include some agents which are no longer authorized for use by FDA at this time. ■