Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial

Abstract

Importance: Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production.

Objective: To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease.

Design, setting, and participants: Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020.

Interventions: Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days.

Main outcomes and measures: The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

Results: Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events.

Conclusions and relevance: In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures.

Trial registration: ClinicalTrials.gov Identifier: NCT04342663.

Figure 1.. Enrollment and Patient Flow

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ^aDid not speak English, lived outside delivery area of the study, or unable to provide data via phone or internet. ^bInterstitial lung disease, immunocompromised, actively suicidal or psychotic, cognitive impairment (dementia or Alzheimer disease), metastatic cancer, or end-stage congestive heart failure. ^cPrednisone dose greater than 20 mg/d (most common exclusionary medication), azithromycin (not allowed at start of the study, but later allowed), hydroxychloroquine (not allowed at start of study, but later allowed), or some immunosuppressant biologic medications (such as belimumab). ^dCOVID-19 suspected and patient either had a negative test result or unable to obtain test. ^eStaff unable to contact potential participants. ^fReceived medication and study supplies, but then research staff were unable to contact participants further. ^gIncluded in analysis but censored early.

Figure 2.. Time to Clinical Deterioration in the Fluvoxamine and Placebo Groups

The median observation time was 15 days (interquartile range, 15-15 days) for the fluvoxamine group and 15 days (interquartile range, 15-15 days) for the placebo group. Study day 0 indicates the day of randomization.