Antidepressant May Cut COVID-Related Hospitalization, Mortality: TOGETHER Published

Esther Landhuis

October 28, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

"Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population," the investigators, led by Gilmar Reis, MD, PhD, Research Division, Cardresearch, Belo Horizonte, Brazil, write.

The findings were published online October 27 in Lancet Global Health. As reported by Medscape Medical News in August, the data were originally published as a preprint.

Alternative Mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID, said co-investigator Angela Reiersen, MD, child psychiatrist at Washington University School of Medicine, St. Louis, Missouri.

Based on cell culture and mouse studies showing effects of the molecule's binding to the sigma-1 receptor in the endoplasmic reticulum, Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Reiersen and colleague psychiatrist Eric Lenze, MD, also from Washington Univ., led the phase 2 trial that initially suggested fluvoxamine's promise as an outpatient medication. They are also co-investigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University in Ontario, Canada, partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post-treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care. 

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, only 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.

Additional Analysis Requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional "per-protocol analysis" that was not specified in the trial's original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

In addition, previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, co-principal investigator Edward Mills, PhD, professor in the Department of Health Research Methods, Evidence, and Impact at McMaster University, noted.

To screen more than 12,000 patients and enroll 4000 in order to test nine interventions, "our total budget was less than $8 million," Mills said. The trial was funded by FastGrants and the Rainwater Charitable Foundation.

"A $10 Medicine"

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is "a $10 medicine that's available and has a very good safety record."

By comparison, a 5-day course of Merck's antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, that data has not been peer reviewed — and molnupiravir is not currently available and has unknown long-term safety implications, Boulware said.

Pharmaceutical companies typically spend tens of millions of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health's ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Boulware, who co-chairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100 mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered Safety, Efficacy Questions

In an accompanying editorial, Otavio Berwanger, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, "some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open," Berwanger writes.

The effects of the drug on reducing both mortality and hospitalizations also "still need addressing," he notes.

"In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme," writes Berwanger.

To Medscape Medical News, he noted that 74% of the Brazil population has currently received at least one dose of a COVID vaccine and 52% has received two doses. In addition, deaths have gone down from 4000 per day during the March-April second wave to about 400 per day. "That is still unfortunate and far from ideal," he said. In total, they have had about 600,000 deaths because of COVID.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID based on the TOGETHER trial data, Berwanger answered, "Not yet."

"I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard," he said.

The TOGETHER trial was funded by Fast Grants and the Rainwater Charitable Foundation. Reiersen and Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Mills reports no relevant financial relationships, as does Boulware — except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

Lancet Glob Health. Published online October 27, 2021. Full text, Editorial

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