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

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

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 difference that was statistically significant.

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.

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

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Article Information

Corresponding Author: Eric J. Lenze, MD, Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, PO Box 8134, St Louis, MO 63110 (lenzee@wustl.edu).

Accepted for Publication: October 29, 2020.

Published Online: November 12, 2020. doi:10.1001/jama.2020.22760

Author Contributions: Dr Lenze had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lenze, Mattar, Zorumski, Schweiger, Nicol, Miller, Yingling, Reiersen.

Acquisition, analysis, or interpretation of data: Lenze, Mattar, Zorumski, Stevens, Nicol, Miller, Yang, Yingling, Avidan, Reiersen.

Drafting of the manuscript: Lenze, Schweiger, Nicol, Yang, Reiersen.

Critical revision of the manuscript for important intellectual content: Lenze, Mattar, Zorumski, Stevens, Schweiger, Nicol, Miller, Yang, Yingling, Avidan.

Statistical analysis: Miller, Yang, Yingling.

Obtained funding: Lenze, Zorumski, Schweiger.

Administrative, technical, or material support: Zorumski, Schweiger, Nicol, Yang, Yingling, Avidan.

Supervision: Lenze, Mattar, Schweiger, Nicol.

Conflict of Interest Disclosures: Dr Lenze reported receiving grants from the Patient-Centered Outcomes Research Institute, Takeda, Alkermes, Janssen, Acadia, and the Barnes Jewish Hospital Foundation; and receiving consulting fees from Janssen and Jazz Pharmaceuticals. Dr Zorumski reported being on the scientific advisory board for and having stock and stock options with Sage Therapeutics; and receiving personal fees from CME Outfitters and JAMA Psychiatry. Dr Nicol reported receiving grants from Alkermes, the Center for Brain Research in Mood Disorders, the Center for Diabetes Translational Research, the Institute for Public Health, the McDonnell Center for Neuroscience, and the Barnes Jewish Hospital Foundation; and serving as a consultant to Sunovion, Alkermes, and Elira. Mr Miller reported receiving research funding from the Patient-Centered Outcomes Research Institute. Dr Avidan reported receiving grants from the COVID-19 Therapeutics Accelerator. No other disclosures were reported.

Funding/Support: This study was supported by the Taylor Family Institute for Innovative Psychiatric Treatment at Washington University and the COVID-19 Early Treatment Fund. Additional support came from the Center for Brain Research in Mood Disorders at Washington University, the Bantly Foundation, and grant UL1TR002345 from the National Institutes of Health.

Role of the Funder/Sponsor: None of the funders/sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients who participated in this study and the COVID-19 clinical trial team of the Healthy Mind Lab (Roz Abdulqadar, BS, Kelly Ahern, BS, Stephanie Brown, Andes Daskalakis-Perez, BA, Leonard Imbula, BSc, Aris Perez, BA, Marissa Rhea, MA, and Jennifer Wulfers, MA; all were compensated for their role). We also thank the Washington University COVID-19 Clinical Studies Committee (William Powderly, MD, and Suresh Vedantham, MD; both were compensated for their role) for their timely review and advice in this study’s design and conduct.

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