The Lancet Global Health: Treatment of COVID-19 with fluvoxamine reduces risk of prolonged hospitalization, finds largest trial to date

• The fluvoxamine arm of the TOGETHER trial, a randomised adaptive platform trial investigating the efficacy of repurposed treatments for COVID-19 among high-risk Brazilian adult outpatients, is the largest trial of the SSRI fluvoxamine as a COVID-19 treatment to date.
• Of the 741 participants who were treated in an emergency setting for COVID-19 after receiving fluvoxamine, 79 required physician treatment for more than six hours or were hospitalised, compared to 119 out of the 756 participants who received the placebo.
• The results represent an important step in understanding the role of fluvoxamine as a treatment for outpatients with COVID-19 and finding inexpensive, widely available, and effective therapies against this disease.

The results of a new randomised clinical trial, published in The Lancet Global Health, have demonstrated that using fluvoxamine to treat high-risk outpatients with early-diagnosed COVID-19 reduced the need for prolonged observation in an emergency setting [1] or hospitalisation, compared to a control group who received a placebo.

This arm of the TOGETHER trial is the largest randomised trial to date to assess the effectiveness of fluvoxamine for patients with COVID-19 in the community. The results represent an important step in understanding the role of fluvoxamine for outpatients with early diagnosed, symptomatic COVID-19 and reinforce the concept that it is possible to generate rapid and high-quality evidence during the pandemic.

“Recent vaccination developments and campaigns have proved to be effective and important in reducing the number of new symptomatic cases, hospitalisations, and deaths due to COVID-19. However, COVID-19 still poses a risk to individuals in countries with low resources and limited access to vaccinations.” Says Dr Edward Mills of McMaster University, co-principal investigator on the trial. “Identifying inexpensive, widely available, and effective therapies against COVID-19 is therefore of great importance, and repurposing existing medications that are widely available and have well-understood safety profiles is of particular interest.” [2]

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI), currently used to treat mental health conditions such as depression and obsessive-compulsive disorders. It was chosen for study as a potential treatment for COVID-19 due to its anti-inflammatory properties. According to Dr Angela Reiersen, Associate Professor of Psychiatry at Washington University in St. Louis and co-author, “Fluvoxamine may reduce the production of inflammatory molecules called cytokines, that can be triggered by SARS-CoV-2 infection.” [2]

The TOGETHER trial is a randomised adaptive platform trial to investigate the efficacy of eight repurposed treatments for COVID-19 among high-risk adult outpatients. The trial began in June 2020 with the fluvoxamine arm beginning in January 2021, recruiting a cohort of Brazilian adults who were symptomatic, had tested positive for COVID-19, were unvaccinated, and had at least one additional criterion for high risk [3]. 741 participants were given 100mg of fluvoxamine twice daily for ten days and 756 participants received a placebo. The trial participants were observed for 28 days post-treatment, with the main outcome of the trial being patients spending more than six hours receiving physician treatment at a specialised COVID-19 emergency setting, or hospitalisation.

Of the 741 participants who received fluvoxamine, 79 required (79/741 [10.6%]) an extended stay for more than six hours in an emergency setting or hospitalisation, compared to 119 out of the 756 (119/756 [15.7%]) participants who received the placebo. These results demonstrated an absolute reduction in the risk of prolonged hospitalisation/prolonged emergency care of 5% with and a relative risk reduction of 32%.

Although mortality was not a primary outcome of the study, in a secondary “per protocol” analysis of patients who took at least 80% of medication doses, there was one death in the fluvoxamine group, compared to 12 in the placebo group.

“Our results are consistent with earlier, smaller trials. 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.” Says Dr Gilmar Reis, co-principal investigator, based in Belo Horizonte, Brazil [2].

The authors acknowledge some limitations in the study. Although fluvoxamine is widely available, it is not on the WHO Essential Medicines List. A closely related SSRI, fluoxetine, is on this list, and it is now crucial to establish if these drugs can be used interchangeably for COVID-19, as well as determining whether combining fluvoxamine with other drugs will provide a larger treatment effect. Additionally, the authors note that the use of interventions, including fluvoxamine, to prevent progression of illness and hospitalisation is critically dependent on reliably identifying individuals at highest risk of deterioration in the early stages of COVID-19 infection.

Writing in a linked comment, Otavio Berwanger of the Academic Research Organisation of Hospital Israelita Albert Einstein, Sao Paulo, Brazil, says: “Despite the important findings from the TOGETHER trial, some questions related to the efficacy and safety of fluvoxamine for patients with COVID-19 remain open. The definitive answer regarding the effects of fluvoxamine on individual outcomes such as mortality and hospitalisations still need addressing. It remains to be determined whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme. Finally, is still unclear whether the results from the TOGETHER trial extend to other outpatient populations with COVID-19, including those without risk factors for disease progression, those who are fully vaccinated, and those infected with the delta variant or other recent variants.”

NOTES TO EDITORS

This study was funded by FastGrants and The Rainwater Foundation. It was conducted by researchers from McMaster University, Hamilton, Ontario, Canada, Washington University in St. Louis, Missouri, USA and CardResearch, Belo Horizonte, Minais Gerais, Brazil.

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[1] This region of Brazil implemented hospital-like services in the emergency settings with 50-80 bed settings, and providing services including oxygenation, sedation, multi-day stays, and mechanical ventilation.

[2] Quote direct from author and cannot be found in the text of the Article.

[3] The high-risk criteria considered included: diabetes mellitus; systemic arterial hypertension requiring at least one oral medication for treatment; known cardiovascular diseases (heart failure, congenital heart disease, valve disease, coronary artery disease, cardiomyopathies being treated, clinically manifested heart disease and with clinical repercussion); symptomatic lung disease and / or being treated (emphysema, fibrosing diseases); symptomatic asthma patients requiring chronic use of agents to 144 control symptoms; smoking; obesity, defined as BMI>30 kg / m2 (weight and height information provided by the patient); transplant patients; patient with stage IV chronic kidney disease or on dialysis; immunosuppressed patients / using corticosteroid therapy (equivalent to at least 10 mg of prednisone per day) and / or immunosuppressive therapy; patients with a history of cancer in the last 0.5 years or undergoing current cancer treatment, or age  50 years; and unvaccinated status.