Fluvoxamine for Outpatient Management of COVID-19 to Prevent Hospitalization
MD, MPH Todd C Lee, MD, MSc Simone Vigod, Émilie Bortolussi-Courval, BSc Ryan Hanula, MD, MPH David R Boulware, MD Eric J Lenze, MD, MPE Angela M Reiersen, MD, MSc Emily G Mcdonald
JAMA Network Open, doi:10.1001/jamanetworkopen.2022.6269
IMPORTANCE Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization. OBJECTIVE To 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 Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.
DATA EXTRACTION AND SYNTHESIS The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects metaanalysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR Յ 1) and moderate association (RR Յ 0.9) with reduced hospitalization.
MAIN OUTCOMES AND MEASURES All-cause hospitalization.
RESULTS This systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%.
CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management (continued) Key Points Question Is early administration of fluvoxamine associated with hospitalization in symptomatic adult outpatients with confirmed COVID-19? Findings In this systematic review and bayesian meta-analysis of 3 clinical trials, which accounted for varying prior probabilities coupled with a frequentist sensitivity analysis, there was a high probability (94.1%-98.6%) that fluvoxamine was associated with a reduced risk for hospitalization, with a frequentist risk ratio of 0.75 (95% CI, 0.58-0.97). Meaning These findings suggest that fluvoxamine, a widely available and..
Author Contributions: Dr Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Additional Information: This study was not registered and a full review protocol was not written because it was initially conducted as a rapid review and then changed to a full systematic review and meta-analysis.
Bhimraj, Morgan, Shumaker, Infectious diseases society of america guidelines on the treatment and management of patients with COVID-19 version 5.5.2, Infectious Diseases Society of America
Core, Zampieri, Fg, Casey, Shankar-Hari et al., Using bayesian methods to augment the interpretation of critical care trials: an overview of theory and example reanalysis of the alveolar recruitment for acute respiratory distress syndrome trial, doi:10.1164/rccm.202006-2381CP
Ezer, Belga, Daneman, Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN phase II randomised controlled trial, BMJ, doi:10.1136/bmj-2021-068060
Ishima, Fujita, Hashimoto, Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells, Eur J Pharmacol, doi:10.1016/j.ejphar.2014.01.064
Lee, Mcdonald, Butler-Laporte, Harrison, Cheng et al., Remdesivir and systemic corticosteroids for the treatment of COVID-19: a bayesian re-analysis, Int J Infect Dis, doi:10.1016/j.ijid.2021.01.065
Lenze, Fluvoxamine for early treatment of COVID-19: a fully-remote, randomized placebo controlled trial
Lenze, Fluvoxamine for early treatment of covid-19: the STOP COVID clinical trials
Naggie, ACTIV-6: COVID-19 outpatient randomized trial to evaluate efficacy of repurposed medications
Page, Mckenzie, Bossuyt, The PRISMA 2020 statement: an updated guideline for reporting systematic reviews, BMJ, doi:10.1136/bmj.n71
Reis, Santos Moreira-Silva, Silva, Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, Lancet Glob Health, doi:10.1016/S2214-109X(21)00448-4
Rosen, Seki, Fernández-Castañeda, Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis, Sci Transl Med, doi:10.1126/scitranslmed.aau5266
Safa, Chong, Effect of fluvoxamine medicine on cytokine level of COVID-19 patients, hospitalized in ICU ward
Seftel, Boulware, Prospective Cohort of fluvoxamine for early treatment of coronavirus disease 19, Open Forum Infect Dis, doi:10.1093/ofid/ofab050
Siripongboonsitti, Effect of combined fluvoxamine with favipiravir versus favipiravir monotherapy in prevention of clinical deterioration among mild to moderate COVID-19 patients monitoring by telemedicine in virtual clinic: open-label randomized controlled trial
Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial, Ann Intern Med, doi:10.7326/M20-4207
Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine: a review of its mechanism of action and its role in COVID-19, Front Pharmacol, doi:10.3389/fphar.2021.652688
Turner, Jackson, Wei, Thompson, Higgins, Predictive distributions for between-study heterogeneity and simple methods for their application in bayesian meta-analysis, Stat Med, doi:10.1002/sim.6381
Wannigama, Randomized-controlled trial of the effectiveness of COVID-19 early treatment in community with fluvoxamine, bromhexine, cyproheptadine, and niclosamide in decreasing recovery time