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. 2023 Jan 24;329(4):296-305.
doi: 10.1001/jama.2022.24100.

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

Matthew W McCarthy  1 , Susanna Naggie  2   3 , David R Boulware  4 , Christopher J Lindsell  5 , Thomas G Stewart  5   6 , G Michael Felker  2   3 , Dushyantha Jayaweera  7 , Mark Sulkowski  8 , Nina Gentile  9 , Carolyn Bramante  4 , Upinder Singh  10 , Rowena J Dolor  2   3 , Juan Ruiz-Unger  11 , Sybil Wilson  2 , Allison DeLong  2 , April Remaly  2 , Rhonda Wilder  2 , Sean Collins  5 , Sarah E Dunsmore  12 , Stacey J Adam  13 , Florence Thicklin  14 , George Hanna  15 , Adit A Ginde  16 , Mario Castro  17 , Kathleen McTigue  18 , Elizabeth Shenkman  19 , Adrian F Hernandez  2   3 ; Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators
Collaborators, Affiliations

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

Matthew W McCarthy et al. JAMA. .

Erratum in

Abstract

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.

Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US.

Design, setting, and participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US.

Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo.

Main outcomes and measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28.

Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups.

Conclusions and relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

Trial registration: ClinicalTrials.gov Identifier: NCT04885530.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Naggie reported receiving grants from Gilead Sciences and AbbVie; receiving personal fees from Pardes Biosciences and Personal Health Insights; serving as a scientific advisor and having stock options in Vir Biotechnology; having stock options and receiving nonfinancial support from Silverback Therapeutics; and serving on committees for Bristol Myers Squibb and PRA. Dr Lindsell reported receiving grants from the US Centers for Disease Control and Prevention and the US Department of Defense; receiving research services from Endpoint Health, bioMerieux, Entegrion, AbbVie, and AstraZeneca; and having a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Stewart reported receiving grants from Duke University. Dr Jayaweera reported receiving grants from the Biomedical Advanced Research and Development Authority, Janssen, ViiV Healthcare Ltd, and Gilead and serving as a consultant to Theratechnologies. Dr Sulkowski reported serving on advisory boards and receiving personal fees from AbbVie, Atea, Antios, Gilead, GlaxoSmithKline, Janssen, Precision Bio, Virion, and ViiV Healthcare Ltd. Dr Bramante reported receiving research support from Apotex. Dr Collins reported receiving personal fees from Vir Biotechnology and Enanta Pharmaceuticals. Dr Hanna reported receiving grants from Biomedical Advanced Research and Development Authority and receiving personal fees from Merck & Co and AbPro. Dr Ginde reported receiving grants from the National Institutes of Health, the US Centers for Disease Control and Prevention, Faron Pharmaceuticals, AbbVie, and the US Department of Defense. Dr Castro reported receiving grants from the National Institutes of Health, the American Lung Association, the Patient-Centered Outcomes Research Institute, AstraZeneca, Gala Therapeutics, GlaxoSmithKline, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, Theravance; receiving personal fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines, and GlaxoSmithKline; having a patent with Aer Therapeutics; and receiving royalties from Elsevier. Dr McTigue reported receiving grants from the University of Pittsburgh, Pfizer, and Janssen Pharmaceuticals. Dr Hernandez reported receiving personal fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Merck, and Cytokinetics and receiving grants from Amgen, Bayer, Boehringer Ingelheim, American Regent, Verily, Merck, Somologic, and Pfizer. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients in the ACTIV-6 Platform Trial Investigating Repurposed Drugs for Nonhospitalized Persons With Mild to Moderate COVID-19
ACTIV-6 indicates Accelerating COVID-19 Therapeutic Interventions and Vaccines. aOne patient met more than 1 of the exclusion criteria. bIn this platform trial with multiple study drugs, participants were able to choose which agents they were willing to potentially take. At the first step of randomization, participants were assigned to receive either placebo or active drug in a ratio of 1:m, where m is the number of study drug groups for which participants were eligible. The more study groups for which a participant was eligible, the greater the chance of receiving the active study drug. Subsequently, participants were randomized among the m study groups with equal probability.
Figure 2.
Figure 2.. Posterior Distribution Effects
The vertical lines represent the estimated mean of the posterior distribution. Posterior density is the relative likelihood of posterior probability distribution. Outcomes with higher posterior density are more likely than outcomes with lower posterior density.
Figure 3.
Figure 3.. Primary Outcome of Time to Sustained Recovery
Sustained recovery was defined as the third day of 3 consecutive days without symptoms. Fifty-two participants were censored for nonresponse and all others were followed up until sustained recovery, death, or the end of 28-day follow-up. The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group.
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Comment in

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