Antidepressant for Mild COVID-19 Prevents Admissions

Fluvoxamine (Luvox) given to high-risk COVID-19 patients outside the hospital helped them avoid spending much time in the hospital for it, the TOGETHER trial from Brazil showed.

The selective serotonin reuptake inhibitor reduced the composite of more than 6 hours of observation in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19 by day 28 compared with placebo in a Bayesian analysis (11% vs 16%; HR 0.68, 95% Bayesian credible interval 0.52-0.88).

The probability of superiority was 99.8%, with a number needed to treat of 20, Gilmar Reis, PhD, of Pontificia Universidade Católica de Minas Gerais, and colleagues reported in Lancet Global Health.

“Given fluvoxamine’s safety, tolerability, ease of use, low cost, and widespread availability, these findings might influence national and international guidelines on the clinical management of COVID-19,” the researchers concluded.

That this inexpensive existing oral drug reduced the need for advanced disease care is especially promising for developing countries, the team noted.

“A 10-day course of fluvoxamine costs approximately US$4 even in well-resourced settings,” Reis and co-authors wrote. “Our study compares favorably with the treatment effects of more expensive treatments including monoclonal antibodies for outpatient treatment.” Potential mechanisms are anti-inflammatory and antiplatelet action, the researchers added.

There’s definitely an unmet need for COVID-19 outpatients, “who comprise the largest population of individuals infected with the SARS-CoV-2, and for whom few effective therapies exist,” agreed Otavio Berwanger, MD, PhD, of the Hospital Israelita Albert Einstein in Sao Paulo, in an accompanying editorial.

However, he cautioned: “Despite the promising results, limitations such as low statistical power and missing data for the primary outcome precluded definitive conclusions about the efficacy of fluvoxamine for the treatment of COVID-19.”

Other concerns were the lack of event adjudication and the inconclusive effects on hospitalization and mortality, Berwanger added.

Mortality came out essentially similar between fluvoxamine and placebo in the intention-to-treat analysis (17 vs 25 deaths, OR 0.68, 95% CI 0.36-1.27) but trended lower in the per-protocol population (OR 0.09, 95% CI 0.01-0.47). Most of the events in the primary composite endpoint (87%) were hospitalizations.

Among secondary endpoints, there were no significant differences in:

  • Viral clearance at day 7
  • Hospitalizations due to COVID
  • All-cause admissions
  • Time to hospitalization
  • Duration of hospital stay
  • Number of days on mechanical ventilation
  • Time to recovery

The adaptive platform trial randomized 1,497 participants to fluvoxamine (100 mg twice daily) or matching placebo for 10 days, starting within 7 days of a positive test for SARS-CoV-2. All the patients were considered at high risk for disease progression based on age 50 or older, diabetes, hypertension, obesity, smoking, immunosuppressive conditions, unvaccinated status, or comorbidities such as cancer, cardiovascular, pulmonary, and kidney disorders.

“Use of interventions, including fluvoxamine, to prevent progression of illness and hospitalization is critically dependent on identifying higher-risk individuals,” the researchers said. “These considerations raise the importance of the development of a validated prediction rule for deterioration in patients in the early stages of COVID-19 infection.”

The treated population was largely unvaccinated, so more data are needed on the effect of fluvoxamine among vaccinated populations, Reis and colleagues added. Also, the closely related selective serotonin reuptake inhibitor fluoxetine is on the WHO Essential Medicines List, so it is “now crucial to establish whether a class effect exists and whether these drugs can be used interchangeably for COVID-19.”

Other questions are whether fluvoxamine “has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” Berwanger wrote. “Finally, it is still unclear whether the results from the TOGETHER trial extend to other outpatient populations with COVID-19, including those without risk factors for disease progression … and those infected with the delta variant or other variants.”

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Disclosures

The trial was supported by Fast Grants and the Rainwater Foundation.

Reis disclosed having been employed by CardResearch; co-authors disclosed having been employed by Platform Life Sciences, Cytel, and Certara, and two are co-inventors on a patent application filed by Washington University for methods of treating COVID-19.

Berwanger disclosed research grants to his institution from AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer-Ingelheim.

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