Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients with COVID-19; The ACTIV-6 Randomized Clinical Trial

Thomas G. Stewart, University of Virginia
Paulina A. Rebolledo, Emory University School of Medicine
Ahmad Mourad, Duke University School of Medicine
Christopher J. Lindsell, Duke University School of Medicine
David R. Boulware, University of Minnesota Medical School
Matthew W. McCarthy, Weill Cornell Medicine
Florence Thicklin, Stakeholder Advisory Committee
Idania T. Garcia Del Sol, L&A Morales Healthcare Inc
Carolyn T. Bramante, University of Minnesota Medical School
Leslie A. Lenert, Medical University of South Carolina
Stephen Lim, LSU Health Sciences Center - New Orleans
John C. Williamson, Wake Forest University School of Medicine
Orlando Quintero Cardona, Stanford University School of Medicine
Jake Scott, Stanford University School of Medicine
Tiffany Schwasinger-Schmidt, University of Kansas School of Medicine - Wichita
Adit A. Ginde, University of Colorado School of Medicine
Mario Castro, UMKC School of Medicine
Dushyantha Jayaweera, University of Miami Leonard M. Miller School of Medicine
Mark Sulkowski, Johns Hopkins University
Nina Gentile, Lewis Katz School of Medicine
Kathleen McTigue, University of Pittsburgh Medical Center
G. Michael Felker, Duke University School of Medicine
Allison Delong, Duke Clinical Research Institute
Rhonda Wilder, Duke Clinical Research Institute
Russell L. Rothman, Vanderbilt University Medical Center
Sean Collins, Vanderbilt University Medical Center
Sarah E. Dunsmore, National Center for Advancing Translational Sciences (NCATS)
Stacey J. Adam, National Institutes of Health (NIH)


Importance; The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective; To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants; The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions; Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures; The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results; Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy =.40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit); 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy =.86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance; Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration; ClinicalTrials.gov Identifier; NCT04885530.