Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation
Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.
The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18–102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52–0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53–0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21–0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36–1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01–0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups.
Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.
FastGrants and The Rainwater Charitable Foundation.
For the Portuguese translation of the abstract see Supplementary Materials section.
Identifying inexpensive, widely available, and effective therapies against COVID-19 is, therefore, of great importance. In particular, repurposing existing medicines that are widely available and with well understood safety profiles, has particular appeal.
Evidence before this study
A search of PubMed on Sept 10, 2021 by means of the following search terms “(randomized OR trial) AND (fluvoxamine OR antidepressants OR selective serotonin reuptake inhibitors OR SSRIs) AND (COVID* OR SARS-CoV-2 OR SARS-CoV)”, with no date or language restrictions identified one observational study that reported a significant association between antidepressant use and reduced risk of intubation or death (hazard ratio 0·56; 95% CI 0·43–0·73, p<0·001) and one randomised clinical trial that reported that adult outpatients with symptomatic COVID-19, treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. In this preliminary randomised trial, 152 participants were randomly assigned to receive 100 mg of fluvoxamine (n=80) or placebo (n=72) three times daily for 15 days; the primary endpoint was clinical deterioration within 15 days of randomisation defined by meeting criteria of shortness of breath, hospitalisation for shortness of breath, pneumonia and oxygen saturation less than 92%, or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.
Added value of this study
TOGETHER is the largest randomised trial to assess the effectiveness of fluvoxamine for patients with COVID-19 in the community. Compared with placebo, patients randomly assigned to fluvoxamine had a lower risk of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.
Implications of all the available evidence
There are few effective therapies for patients with COVID-19 in the community. Results provide compelling evidence of fluvoxamine’s benefit in reducing acute morbidity from COVID-19 illness.
There are several potential mechanisms for fluvoxamine in treatment of COVID-19 illness, including anti-inflammatory and possible antiviral effects.
A small placebo-controlled, randomised trial has raised the possibility that fluvoxamine might reduce the risk of clinical deterioration in outpatients with COVID-19, suggesting the need for larger randomised, placebo-controlled studies.
Among eight different interventions evaluated in this platform trial, we report here on the clinical evaluation of fluvoxamine by means of a concurrent placebo control group.
The trial was designed and done in partnership with local public health authorities from 11 participating cities in Brazil to simultaneously test potential treatments for early disease by means of a master protocol. A master protocol defines prospective decision criteria for discontinuing interventions for futility, stopping because of superiority against placebo, or adding new interventions. Interventions evaluated in the TOGETHER trial, thus far, include, hydroxychloroquine (protocol 1), lopinavir–ritonavir (protocol 1),
metformin, ivermectin, fluvoxamine, doxasozin, and pegylated interferon lambda versus matching placebos (protocol 2). The TOGETHER trial is centrally coordinated by Platform Life Sciences (Vancouver, Canada) with local implementation provided by Cardresearch (Belo Horizonte, Brazil). Statistical analyses were done by Cytel (Waltham, MA, USA).