Fluvoxamine may prevent COVID-19 hospitalization

Treatment with the selective serotonin reuptake inhibitor fluvoxamine may prevent hospitalization in outpatients presenting with symptoms of COVID-19 who have a high risk for disease progression, according to results of the TOGETHER trial.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” noted the authors. “[The] results provide compelling evidence of fluvoxamine’s benefit in reducing acute morbidity from COVID-19 illness,” they said.

The study, conducted at 11 centres in Brazil, included 1,497 adults (median age 50 years, 58 percent female, 95 percent mixed race) who presented at outpatient care with symptomatic, laboratory-confirmed SARS-CoV-2 infection (symptoms within 7 days of screening) and who had risk factors for progression to severe disease. They were randomized 1:1 to receive fluvoxamine (100 mg BID for 10 days) or placebo in addition to standard of care.

Hospitalization (retention in a COVID-19 emergency setting for >6 hours observation or transfer to tertiary hospital due to COVID-19) by 28 days post-randomization was less common among patients in the fluvoxamine compared with the placebo group (intention-to-treat [ITT] population; 11 percent vs 16 percent; relative risk [RR], 0.68, 95 percent Bayesian credible interval [BCI], 0.52–0.88). Eighty-seven percent of the events were hospitalizations. [Lancet Glob Health 2021;doi:10.1016/S2214-109X(21)00448-4]

With a risk difference of 5 percent between groups, the probability of superiority of fluvoxamine over placebo of 99.8 percent exceeded the prespecified superiority threshold of 97.6 percent, said the authors. Randomization was stopped prematurely for superiority.

The results were consistent in the modified ITT analysis comprising patients who received treatment for ≥24 hours before a primary outcome event (RR, 0.69, 95 percent BCI, 0.53–0.90). However, the difference between groups was more pronounced in the per-protocol analysis which comprised patients with >80 percent adherence to treatment (RR, 0.34, 95 percent BCI, 0.21–0.54).

Viral clearance at day 7 did not significantly differ between the fluvoxamine and placebo groups (19 percent vs 26 percent; odds ratio [OR], 0.67; p=0.090), nor did hospitalizations for COVID-19 (10 percent vs 13 percent; OR, 0.77; p=0.10) or all-cause hospitalizations (10 percent vs 13 percent; OR, 0.76; p=0.088). There was also no significant between-group difference pertaining to time to hospitalization (median 5 days in each group; hazard ratio [HR], 0.79; p=0.11), duration of hospitalization (median 8 vs 6 days; p=0.059), or days on mechanical ventilation (median 5.5 vs 6.5 days; p=0.90). Time to recovery (p=0.79) and the PROMIS Global Physical (p=0.55) or Mental Scale (p=0.32) were also comparable between groups.

While mortality did not significantly differ between groups in the ITT analysis (n=17 vs 25; OR, 0.69; p=0.24), there were significantly fewer deaths in the fluvoxamine vs placebo group in the per-protocol analysis (n=1 vs 12; OR, 0.09, 95 percent CI, 0.01–0.47; p=0.022).

The number of treatment-emergent adverse events (AEs) also did not significantly differ between patients in the fluvoxamine and placebo groups, with 84 and 64 patients, respectively, stopping assigned treatments due to tolerability issues.

“The absolute number of serious AEs associated with fluvoxamine was lower than for placebo and … lower respiratory tract infections were reported less frequently in patients in the fluvoxamine group than those in the placebo group,” the authors pointed out.

“Recent vaccination developments and campaigns have proved to be effective and important in reducing the number of new symptomatic cases, hospitalizations, and deaths due to COVID-19,” said co-principal investigator Professor Edward Mills from McMaster University, Hamilton, Ontario, Canada.

Issues with production, allocation, and cost of COVID-19 preventative vaccines, especially in low-resource settings, highlight the need for “inexpensive, widely available, and effective therapies against COVID-19,” particularly those that already have “well-understood safety profiles,” said the authors.

“Given fluvoxamine’s safety, tolerability, ease of use, low cost, and widespread availability, these findings may have an important influence on national and international guidelines on clinical management of COVID-19,” said co-principal investigator Dr Gilmar Reis from Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil.

The authors suggested that the anti-inflammatory or antiplatelet activity of fluvoxamine, or its ability to increase plasma melatonin levels, may explain its effect in this setting, though the exact mechanism remains unknown.

“[Despite the positive findings,] the definitive answer regarding the effects of fluvoxamine on individual outcomes such as mortality and hospitalizations still needs addressing,” noted Professor Otavio Berwanger from the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, in a commentary. [Lancet Glob Health 2021;doi:10.1016/S2214-109X(21)00501-5]

The effect of fluvoxamine in combination with other COVID-19 therapies, in patients without risk factors for disease progression, on the delta or newer variants, and in fully vaccinated patients also needs to be ascertained, he said.