Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Authors

Thomas G Stewart, Paulina A Rebolledo, Ahmad Mourad, Christopher J Lindsell, David R Boulware, Matthew W McCarthy, Florence Thicklin, Idania T Garcia Del Sol, Carolyn T Bramante, Leslie A Lenert, Stephen Lim, John C Williamson, Orlando Quintero Cardona, Jake Scott, Tiffany Schwasinger-Schmidt, Adit A Ginde, Mario Castro, Dushyantha Jayaweera, Mark Sulkowski, Nina Gentile, Kathleen McTigue, G Michael Felker, Allison DeLong, Rhonda Wilder, Russell L Rothman, Sean Collins, Sarah E Dunsmore, Stacey J Adam, George J Hanna, Elizabeth Shenkman, Adrian F Hernandez, Susanna Naggie,

Full Abstract

• 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.

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