Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

Abstract

ImportanceThe effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.ObjectiveTo 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 ParticipantsThe 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.InterventionsParticipants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo.Main Outcomes and MeasuresThe 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.ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT04885530

Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes

“…Some limitations must be acknowledged such as the monocentric setting of the study, the open-label, retrospective, observational design, with a partial consideration of confounding variables that might concomitantly affect the inflammatory status and depressive psychopathology, and the lack of a control group (either placebo or other antidepressants). Indeed, the antidepressant fluvoxamine, which preliminarily proved to be efficacious in managing SARS-CoV-2 infection outcomes ( Boretti, 2022 ), turned out to show no significant effects in a subsequent placebo-controlled randomized clinical trial ( McCarthy et al, 2023 ).…”

Overview of the potential use of fluvoxamine for COVID-19 and long COVID

“…Then, fluvoxamine (100 mg twice daily) or placebo was administered as tolerated until day 15 This study was terminated early for futility No benefit Reis et al (2022) [ 66 ] TOGETHER Brazil High-risk symptomatic unvaccinated patients with COVID-19 Fluvoxamine (100 mg twice daily) (n = 741) and placebo (n = 756) for 10 days Fluvoxamine group showed significantly lower proportion of emergency setting for more than 6 h or transferred to tertiary hospital due to COVID-19 compared with placebo group Benefit Seo et al (2022) [ 70 ] Korea Patients with mild or moderate COVID-19 who were admitted to the community treatment centers Fluvoxamine (50 mg) (n = 26) or placebo (n = 26) was administered on day 1. Then, fluvoxamine (100 mg twice daily for about 10 days) or placebo was administered for tolerance until discharge from the community treatment centers A single-blind trial showed that there was no significant differences in clinical deterioration between the fluvoxamine group and placebo group No benefit Bramante et al (2022) [ 71 ] COVID-OUT USA Patients with COVID-19 Fluvoxamine (50 mg twice daily) (n = 334) and placebo (n = 327) for 14 days Fluvoxamine did not prevent the primary events such as hypoxemia, an emergency department visit, hospitalization, or death associated with COVID-19 No benefit McCarthy et al (2023) [ 72 ] ACTIV-6 USA Outpatients with mild to moderate COVID-19 Fluvoxamine (50 mg twice daily) (n = 674) and placebo (n = 614) for 10 days The median time to sustained recovery was 12 days in the fluvoxamine group and 13 days in the placebo group. There was no significant difference between the two groups No benefit …”

“…In 2023, McCarthy et al [ 72 ] reported the results of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial (Table 2 ). Outpatients with mild to moderate COVID-19 (n = 1288) were randomly assigned to the fluvoxamine group (50 mg twice daily for 10 days; n = 674) and the placebo group (n = 614).…”

“…The medial time to sustained recovery was 12 days (interquartile range [IQR], 11–14 days) in the fluvoxamine group and 13 days (IQR, 12–13 days) in the placebo group, with no significant difference between these two groups. The results of this study showed that fluvoxamine did not improve the time to sustained recovery in outpatients with mild to moderate COVID-19 [ 72 ].…”

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19

“…Trials of some drugs suggest possible benefit by reducing emergency department (ED) visits or hospitalizations, including fluvoxamine dosed at 100 mg twice daily and immediate-release metformin . Others have failed to show a reduction in ED visits or hospitalizations, such as fluvoxamine 50 mg twice daily . Although recently completed trials benefit from the increasing representation of vaccinated people, which is more relevant to the pandemic’s current state, the results have not affected treatment guidelines largely due to study design limitations, including definitions of outcomes that were of unclear significance in the US health care setting …”