Updated: Sep 19, 2021
Question Does fluvoxamine, a selective serotonin reuptake inhibitor and σ-1 receptor agonist, prevent clinical deterioration in outpatients with acute coronavirus disease 2019 (COVID-19)?
Findings In this randomized trial that included 152 adult outpatients with confirmed COVID-19 and symptom onset within 7 days, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo over 15 days, a statistically significant difference.
Meaning In this preliminary study, adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days; however, determination of clinical efficacy would require larger randomized trials with more definitive outcome measures.
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 the 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 infections, 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 a 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  years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and 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 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
Coronavirus disease 2019 (COVID-19), caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in serious illness leading to hospitalization, intensive care unit admission, and death. Clinical deterioration typically occurs during the second week of illness. Early studies of COVID-19 found that hospitalization most often occurs within 8 to 10 days of initially mild to moderate symptoms. Further evidence suggested that lung damage from COVID-19 was related to an excessive inflammatory response, prompting numerous trials of immunomodulatory drugs.
A potential mechanism for immune modulation is the σ-1 receptor (S1R) agonist. The S1R is an endoplasmic reticulum chaperone protein with various cellular functions, including regulation of cytokine production through its interaction with the endoplasmic reticulum stress sensor inositol-requiring enzyme 1α (IRE1). Previous studies have shown that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with a high affinity for the S1R, reduced damaging aspects of the inflammatory response during sepsis through the S1R-IRE1 pathway, and decreased shock in murine sepsis models.
Fluvoxamine is a strong S1R agonist, is highly lipophilic, and has rapid intracellular uptake. This study tested whether fluvoxamine, given as early treatment in individuals with mild COVID-19 illness, may prevent clinical deterioration.
This was a double-blind, placebo-controlled, randomized clinical trial that compared fluvoxamine with placebo in adult outpatients with confirmed SARS-CoV-2 infection. The trial protocol and statistical analysis plan appear in Supplement 1. The study was approved by the institutional review board at Washington University in St Louis and was conducted in compliance with the Declaration of Helsinki, the Good Clinical Practice guidelines, and local regulatory requirements. All participants provided informed consent via e-consent or written consent.
This trial was conducted in the greater St Louis metropolitan area (eastern Missouri and southern Illinois). Patients were recruited from April 10, 2020, to August 5, 2020. The 30-day post-randomization follow-up assessment was completed on September 19, 2020. This was a fully remote (contactless) clinical trial Participants were recruited via electronic health records, physician and other health professional referrals, study advertisements near COVID-19 testing centers and in emergency departments, referrals by colleagues, a study website, and communication in local television and newspapers. Participants were enrolled without regard to sex, race, ethnicity, or religion. Potential participants underwent screenings by email and phone, and provided informed consent, typically electronically.
Study supplies were delivered to self-quarantined study patients as a package left at their door and the study materials consisted of the study medication, an oxygen saturation monitor, an automated blood pressure monitor, and a thermometer. Participants then self-assessed using the equipment provided and confirmed vital signs within range (systolic blood pressure between 80 mm Hg and 200 mm Hg, diastolic blood pressure between 40 mm Hg and 120 mm Hg, and pulse rate between 50 beats/min and 120 beats/min), pregnancy status when indicated, and oxygen saturation of 92% or greater. Study staff called participants informed them of eligibility and instructed them to take the study medication. The study medication was targeted to start on the same day that participants were first contacted and screened by the research team.