Adult outpatients with symptomatic coronavirus disease 2019 (COVID-19) treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days, according to a preliminary study published in the Journal of the American Medical Association.
However, the researchers led by Eric J Lenze, MD, Washington University in St Louis, St Louis, Missouri, cautioned that “the study was limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomised trials with more definitive outcome measures.”
A total of non-hospitalised 152 adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with symptom onset within 7 days and oxygen saturation of 92% or greater were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10 to August 5, 2020. The mean age of the participants was 46 years and 72% were females.
Participants were randomly assigned to receive a dose of 50 mg of fluvoxamine (or matching placebo) in the evening immediately after the baseline assessment and confirmation of eligibility, then for 2 days at a dose of 100 mg twice daily as tolerated, and then increasing to a dose of 100 mg 3 times daily as tolerated through day 15. The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of shortness of breath or hospitalization for shortness of breath or pneumonia, and oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. The final date of follow-up was September 19, 2020.
Study data showed that clinical deterioration occurred in none of 80 patients in the fluvoxamine group compared to 6 of 72 patients in the placebo group (absolute difference, 8.7%; 95% confidence interval [CI], 1.8%-16.4% from survival analysis; log-rank P = .009). The fluvoxamine group reported 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. Pneumonia and gastrointestinal symptoms such as nausea and vomiting occurred more often in the placebo group compared with those who received fluvoxamine.
In the placebo group, cases of clinical deterioration ranged from 1 to 7 days after randomization. Four of 6 patients were hospitalised for COVID-19 illness, with the length of stay ranging from 4 to 21 days. One patient required mechanical ventilation for 10 days but no patients died.
“The study was prompted by a hypothesis involving the influence of fluvoxamine on the σ-1 receptor-inositol-requiring enzyme 1α (S1R-IRE1) pathway. Anti-inflammatory (cytokine reduction) actions resulting from S1R activation would fit with recent findings of benefits of other anti-inflammatory drugs, such as colchicine and corticosteroids, for COVID-19,” the authors explained. “Alternative mechanisms of a potential fluvoxamine benefit include direct antiviral effects via its lysosomotropic properties, modulation of the effect of IRE1 effects on autophagy, and selective serotonin reuptake inhibitors (SSRI) inhibition of platelet activation.”
“The potential advantages of fluvoxamine for outpatient treatment of COVID-19 include its safety, widespread availability, low cost, and oral administration. Fluvoxamine does not promote QT prolongation unlike other SSRIs,” the authors noted. However, they pointed out that fluvoxamine has adverse effects and can cause drug-drug interactions, particularly via inhibition of cytochromes P450 1A2 and 2C19.
On the other hand, the authors acknowledged that the small number of end point events makes the findings “extremely fragile” and that it is possible that the differences in clinical deterioration may have been a reflection of the comparative baseline distributions of oxygen saturation rather than an effect of treatment.