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

Thomas G Stewart et al. JAMA. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Stewart reported receiving grants from NIH during the conduct of the study and being is contracted to serve on a data monitoring committee for trials sponsored by Eli Lilly. Dr Lindsell reported receiving grants from NCATS to institution during the conduct of the study and grants to the institution from NIH, Department of Defense, and CDC; providing research services for Biomeme, bioMerieux, AstraZeneca, Endpoint Health, Entegrion, Cytokinetics, and Novartis outside the submitted work and having a a patent for risk prediction in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center and stock options in Bioscape Digital unrelated to the current work. Dr Lenert reported receiving grants from Patient Centered Outcomes Research Institute and the National Institutes of Health during the conduct of the study. Dr Lim reported receiving grants from NIH during the conduct of the study. Dr Williamson reported receiving grants from National Center for Advancing Translational Sciences during the conduct of the study. Dr Schwasinger-Schmidt reported receiving grants from National Institute of Health during the conduct of the study and receiving grants from Eisai, Allergan, Janssen, AstraZeneca, Sanofi, Axsome, Johnson & Johnson, Moderna, Bellus, Shanogi, and John Hopkins University outside the submitted work. Dr Ginde reported receiving grants from NIH, Department of Defense, CDC, Faron Pharmaceuticals, and AbbVie outside the submitted work. Dr Castro reported receiving grants from NIH, ALA, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Pulmatrix, Sanofi, Shionogi, Theravance, Teva, Regeneron, Amgen, Aer Therapeutics, Merck, Arrowhead Pharmaceuticals, Allakos, OM PHarma, Pfizer, and Pioneering Medicines and personal fees from AstraZeneca, Genentech, GSK, Novartis, and Sanofi outside the submitted work. Dr Jayaweera reported receiving grants from NIH during the conduct of the study and grants from Gilead Pharmaceuticals and Janssen Pharmaceutical and personal fees from CCO outside the submitted work. Dr Sulkowski reported receiving personal fees from AbbVie, Aligos, Atea, Gilead, Immunocore, GSK, Galapagos, Precision Bioscience, and Virion and grants from Vir and NIH (No. K24DA034621) outside the submitted work. Dr McTigue reported having a research contract provided to the University of Pittsburgh from the CDC and receiving grants provided to the University of Pittsburgh via Penn State outside the submitted work. Dr Rothman reported receiving grants from NIH during the conduct of the study and grants from PCORI, NIH, and AHRQ outside the submitted work. Dr Collins reported receiving personal fees from Enanta Pharmaceuticals outside the submitted work. Dr Hanna reported receiving grants from US Biomedical Advanced Research & Development Authority contract to Tunnell Government Services for consulting services during the conduct of the study and personal fees from Merck and AbPro outside the submitted work. Dr Hernandez reported receiving grants from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Verily outside the submitted work. Dr Naggie reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and receiving grants from Gilead Sciences and AbbVie; receiving personal fees from Pardes Biosciences and Silverback Therapeutics for consulting; serving as a scientific advisor for and having stock options in Vir Biotechnology; receiving personal fees from and serving on a data and safety monitoring board for Personal Health Insights; and serving on an event adjudication committee for Bristol Myers Squibb/PRA Health Sciences outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in a Study of Higher-Dose Fluvoxamine in Mild to Moderate COVID-19
MAOI indicates monoamine oxidase inhibitors; SNRI, serotonin and norepinephrine reuptake inhibitors; and SSRI, selective serotonin reuptake inhibitors. aIn this platform trial with multiple study drugs, participants were able to choose what agents they were willing to be randomized to receive. bNo additional study treatment groups were open while participants were enrolled in this study group; participants were randomized between fluvoxamine and matched placebo.
Figure 2.
Figure 2.. Primary Outcome of Time to Sustained Recovery
Figure 3.
Figure 3.. Time to Sustained Recovery, Health Care Use, and Mean Time Unwell
See this image and copyright information in PMC

Comment in

References

    1. Venkatesan P. Repurposing drugs for treatment of COVID-19. Lancet Respir Med. 2021;9(7):e63. doi:10.1016/S2213-2600(21)00270-8 - DOI - PMC - PubMed
    1. Bramante CT, Huling JD, Tignanelli CJ, et al. ; COVID-OUT Trial Team . Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med. 2022;387(7):599-610. doi:10.1056/NEJMoa2201662 - DOI - PMC - PubMed
    1. Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme VV. Fluvoxamine: a review of its mechanism of action and its role in COVID-19. Front Pharmacol. 2021;12:652688. doi:10.3389/fphar.2021.652688 - DOI - PMC - PubMed
    1. COVID-19 Treatment Guidelines . National Institutes of Health. Accessed September 5, 2023. https://www.covid19treatmentguidelines.nih.gov/
    1. Lenze EJ, Mattar C, Zorumski CF, et al. . Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292-2300. doi:10.1001/jama.2020.22760 - DOI - PMC - PubMed

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