Fluvoxamine for Outpatient COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-Analysis

  1. Todd C. Lee
  2. Simone Vigod
  3. Émilie Bortolussi-Courval
  4. Ryan Hanula
  5. David R. Boulware
  6. Eric J. Lenze
  7. Angela M. Reiersen
  8. Emily G. McDonald

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Abstract

Importance

Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly therapies that prevent hospitalization.

Objective

Perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.

Data Sources

World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.

Study Selection

Completed outpatient trials with available results which compared fluvoxamine to placebo.

Data Extraction and Synthesis

We followed the PRISMA 2020 guidelines. We extracted study details in terms of inclusion criteria, trial demographics and the pre-specified outcome of all-cause hospitalization. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool. We conducted a frequentist random effects meta-analysis, as well as two sensitivity analyses using a Bayesian random effects meta-analysis with different estimates of prior probability: a weakly neutral prior (50% chance of efficacy with 95% confidence interval for Risk Ratio [RR] between 0.5 and 2) and a moderately optimistic prior (85% chance of efficacy). We contextualized the results by estimating the probability of any effect (RR ≤1) and moderate effect (RR ≤0.9) on reducing hospitalization.

Main Outcome(s) and Measure(s)

All cause hospitalization.

Results

2196 participants were included from 3 identified trials. The risk ratios for hospitalization were 0.75 (95%CI, 0.57-0.97) for the frequentist analysis, 0.78 (95%CI 0.58-1.08) for the Bayesian weakly neutral prior, and 0.73 (95%CI, 0.53-1.01) for the Bayesian moderately optimistic prior. Depending on the scenario, the probability of any effect on hospitalization ranged from 94.1% to 98.3% and a moderate effect from 81.6% to 91.1%.

Conclusions and Relevance

Under a variety of assumptions, fluvoxamine shows a high probability of preventing hospitalization in outpatients with COVID-19. While ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates, fluvoxamine could be recommended as a treatment option, particularly in resource-limited settings or persons without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.

Key Points

Question

Does early administration of fluvoxamine prevent hospitalization in symptomatic adult outpatients with confirmed COVID-19?

Findings

In this meta-analysis with Bayesian sensitivity analyses that accounted for varying prior probabilities, there was a high probability (94.1% to 98.3%) that fluvoxamine reduces hospitalization with frequentist risk ratio of 0.75 (95%CI 0.57-0.97).

Meaning

Fluvoxamine is a widely available and inexpensive option that prevents hospitalization in patients with early COVID-19 based on randomized controlled trial evidence to date.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.12.17.21268008: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationAssessment of Bias: Two independent reviewers assessed each study for bias using the Cochrane risk-of-bias 2 tool for randomized trials.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Assessment of Bias: Two independent reviewers assessed each study for bias using the Cochrane risk-of-bias 2 tool for randomized trials.
    Cochrane risk-of-bias
    suggested: None
    The forest plot for the random effects meta-analysis and graphs of the prior and posterior probability distributions based on the pooled RRs were created with STATA version 17 (StataCorp, USA).
    STATA
    suggested: (Stata, RRID:SCR_012763)
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations include variability in healthcare practices, resource availability, and circulating variants between trials, leading to differences in the baseline event rates and the associated absolute risk reduction. While we have attempted to correct for subjectivity by limiting this analysis to hospitalization, indeed hospitalization decisions may vary between geographic areas and even time points based on systemic burden. Nonetheless, all-cause hospitalization is the most common important outcome of outpatient COVID-19 trials because ICU admission or death would require studies that were prohibitively large. Additionally, all three trials excluded fully vaccinated individuals, whose rates of hospitalization are greatly reduced, and therefore any estimates of absolute effect size would likely be an overestimate in vaccinated patients. Another limitation is the inclusion of only 3 trials to date. Using a living systematic review approach will address this clinical question. This is planned in order to address this concern and to rapidly incorporate emerging evidence. Ongoing randomized controlled trials of fluvoxamine should continue, particularly those studying lower 50mg doses (which will be better tolerated), evaluating efficacy in vaccinated individuals, or studying the related SSRI fluoxetine which is on the World Health Organization’s list of essential medications. In the meantime, fluvoxamine is an immediately available, safe, and inexpensive treatment option with a hi...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04342663CompletedA Double-blind, Placebo-controlled Clinical Trial of Fluvoxa…
    NCT04668950CompletedFluvoxamine for Early Treatment of Covid-19 (Stop Covid 2)
    NCT04727424RecruitingRepurposed Approved and Under Development Therapies for Pati…
    NCT04510194RecruitingCOVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infecti…
    NCT04718480RecruitingFluvoxamine Administration in Moderate SARS-CoV-2 (COVID-19)…
    NCT04885530RecruitingACTIV-6: COVID-19 Study of Repurposed Medications
    NCT05087381RecruitingRandomized-controlled Trial of the Effectiveness of COVID-19…
    NCT04711863SuspendedFluvoxamine for Adults With Mild to Moderate COVID-19

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.12.17.21268008 on medRxiv