Effect of Higher-Dose Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial

BackgroundThe impact of fluvoxamine in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) remains uncertain. Our objective was to assess the effectiveness of fluvoxamine 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. MethodsThe 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, 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were age [≥]30 years with confirmed SARS-CoV-2 infection and [≥]2 acute COVID-19 symptoms for [≤]7 days. Participants were randomized to receive fluvoxamine 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days or to placebo. 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 clinical progression scale; and difference in mean time unwell. ResultsAmong participants who were randomized and received study drug, the median age was 50 years (IQR 40-60), 66% were female, 45% identified as Hispanic/Latino, and 77% reported [≥]2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09; P(efficacy) = 0.4]). Additionally, unadjusted, median time to sustained recovery was 10 days (95% CI 10-11) in both the intervention and placebo group. No deaths were reported. Thirty-five participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 14 in the fluvoxamine group compared with 21 in the placebo group (HR 0.69; 95% CrI 0.27-1.21; P(efficacy)=0.86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo). ConclusionsAmong outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial RegistrationClinicalTrials.gov (NCT04885530).