BACKGROUND AND PURPOSE: 

• Reis et al. (Lancet Global Health, 2021) assessed the efficacy of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), vs placebo in preventing COVID-19-related hospitalization  

METHODS: 

• Placebo-controlled, randomized, adaptive platform trial 
  • 11 participating cities in Brazil   
• Participants 
  • Symptomatic adults with confirmed SARS-CoV-2 infection 
  • High-risk: Having a known risk factor for progression to severe disease 
• Interventions 
  • Fluvoxamine: 100 mg twice daily for 10 days 
  • Placebo 
• Study design 
  • All trial team, site staff, and patients were masked to treatment allocation 
  • Primary outcome based on intention to treat 
  • Modified intention to treat explored patients receiving at least 24 hours of treatment before a primary outcome event  
  • Per-protocol analysis explored patients with a high-level adherence (>80%) 
  • A Bayesian analytic framework was used to establish the effects along with probability of success of intervention compared with placebo 
• Primary outcome  
  • A composite endpoint of hospitalization: Either retention in a COVID-19 emergency setting for >6 hours or transfer to tertiary hospital due to COVID-19 
  • Outcome occurred within 28 days of randomization  

RESULTS: 

• Fluvoxamine: 741 patients | Placebo: 756 patients 
  • Trial was stopped early for superiority 
  • Mean (range) age participants 50 (18 to 102) years | 58% female 
• The proportion of patients with the primary composite outcome was lower for the fluvoxamine group 
  • Fluvoxamine: 11% 
  • Placebo: 16% 
  • Relative risk (RR) 0.68 (95% Bayesian credible interval [BCI], 0.52 to 0.88) 
  • Probability of superiority: 99.8% 
• Of the composite primary outcome events, 87% were hospitalizations 
• Findings for the primary outcome were  
  • Similar for the modified intention-to-treat analysis 
    • RR 0.69 (95% BCI, 0.53 to 0.90) 
  • Larger for the per-protocol analysis 
    • RR 0.34 (95% BCI, 0.21 to 0.54) 
• Deaths in the primary intention-to-treat analysis 
  • Fluvoxamine: 17 
  • Placebo: 25 
  • OR 0.68 (95% CI, 0.36 to 1.27) 
• Deaths in the per-protocol population 
  • Fluvoxamine: 1 
  • Placebo: 12 
  • OR 0.09 (95% CI, 0.01 to 0.47) 
• There were no significant differences in number of adverse events due to treatment among patients in either group 

CONCLUSION: 

• High-risk outpatients with confirmed COVID-19 had reduced hospitalization needs when treated with fluvoxamine (100 mg twice daily for 10 days) 
• The mechanism underlying the benefit of this SSRI is unknown but the following hypotheses have been suggested 
  • Fluvoxamine has anti-inflammatory action through activation of the protein S1R that regulates cytokine production  
  • Fluvoxamine has antiplatelet activity 
• The authors state 

We found a clinically important absolute risk reduction of 5.0%, and 32% RR reduction, on the primary outcome of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19, consequent on the administration of fluvoxamine for 10 days 

Learn More – Primary Sources: 

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized, platform clinical trial 

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