Late treatment low risk population RCT showing lower progression to hospitalization or urgent care/ER visits with fluvoxamine, without statistical significance.There was no mortality and only three hospitalizations. Authors provide no details on the cause of hospitalization, but they appear to be unrelated to COVID-19. eFigure 5 shows no COVID-19 clinical progression to hospitalization (note that a hospitalization can be seen in the equivalent plot for the low dose arm), and the text indicates that the "COVID clinical progression scale simplified into a self-reported evaluation of home levels (limited vs not)".Note that the urgent care/ER visit outcome is also likely diluted due to inclusion of all-cause events, and could be statistically significant for only COVID-19 events.The sustained recovery outcome, which shows no difference, was a post-hoc creation used to hide efficacy for ivermectin, and is not logical for evaluating efficacy in this trial. The definition includes any minor symptom within a three day period - e.g., any minor cough, headache, body ache, or fatigue that occurs in a three day period, regardless of cause, results in the treatment being considered a failure. For example, late treatment that is effective at minimizing progression, but has no improvement in resolution of cough, would not be detected. (Authors even use the end of the three day period to further minimize efficacy).Late treatment - median 5 days, 75% 4+ days, 25% 7+ days, up to 12 days.Also see Naggie for many issues with this trial, and McCarthy for the lower dose arm.
risk of progression, 31.0% lower, RR 0.69, p = 0.34, treatment 14 of 589 (2.4%), control 21 of 586 (3.6%), NNT 83, adjusted per study, urgent or emergency care visits, hospitalizations, or death.
clinical progression, 34.0% lower, OR 0.66, p = 0.32, treatment 589, control 586, mid-recovery, day 14, RR approximated with OR.
clinical progression, 15.0% higher, OR 1.15, p = 0.68, treatment 589, control 586, day 7, RR approximated with OR.
clinical progression, 6.0% lower, OR 0.94, p = 0.90, treatment 589, control 586, day 28, RR approximated with OR.
risk of no recovery, 1.0% higher, HR 1.01, p = 0.86, treatment 589, control 586, inverted to make HR<1 favor treatment, post-hoc primary outcome.
risk of hospitalization, 49.0% lower, RR 0.51, p = 0.59, treatment 1 of 589 (0.2%), control 2 of 586 (0.3%), NNT 583, non-COVID-19 hospitalization, day 28.
Abstract: medRxiv preprint doi: https://doi.org/10.1101/2023.09.12.23295424; this version posted September 13, 2023. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.
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Effect of Higher-Dose Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients with
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Mild to Moderate COVID-19: A Randomized Clinical Trial
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The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and
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Investigators
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Address for correspondence: Susanna Naggie, MD, MHS, Duke Clinical Research Institute, Duke
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University School of Medicine, 300 West Morgan St, Suite 800, Durham, NC 27701. Email:
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susanna.naggie@duke.edu.
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2023.09.12.23295424; this version posted September 13, 2023. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.
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Abstract
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Background: The impact of fluvoxamine in reducing symptom duration among outpatients with mild to
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moderate coronavirus disease 2019 (COVID-19) remains uncertain. Our objective was to assess the
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effectiveness of fluvoxamine 100 mg twice daily, compared with placebo, for treating mild to moderate
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COVID-19.
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Methods: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for
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mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, 1175 participants were
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enrolled at 103 US sites for evaluating fluvoxamine; participants were age ≥30 years with confirmed
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SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days. Participants were randomized to
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receive fluvoxamine 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days or
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to placebo. The primary outcome was time to sustained recovery (defined as at least 3 consecutive days
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without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a
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composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical
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progression scale; and difference in mean time unwell.
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Results: Among participants who were randomized and received study drug, the median age was 50 years
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(IQR 40-60), 66% were female, 45% identified as Hispanic/Latino, and 77% reported ≥2 doses of a
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SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo,
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differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95%
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credible interval, 0.89-1.09; P(efficacy) = 0.4]). Additionally, unadjusted, median time to sustained
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recovery was 10 days (95% CI 10-11) in both the intervention and placebo group. No deaths were
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reported. Thirty-five participants reported healthcare utilization events (a priori defined as death,
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hospitalization, emergency department/urgent care visit); 14 in the fluvoxamine group compared with 21
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in the placebo group (HR 0.69; 95% CrI 0.27–1.21;..
Late treatment is less effective
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