In the largest randomised clinical trial to date, researchers have demonstrated that the drug fluvoxamine is proficient at reducing the risk of prolonged hospitalisation from COVID-19.
The findings from the TOGETHER trial, which are published in The Lancet Global Health, elucidated that using fluvoxamine to treat high-risk outpatients with early-diagnosed COVID-19 successfully mitigated the need for a prolonged stay in an emergency setting compared to a control group who received a placebo.
The Together trial began in June 2020 and is a randomised adaptive platform trial aimed at investigating the efficacy of eight repurposed medications for treating high-risk COVID-19 adult outpatients. This fluvoxamine aspect of the TOGETHER trial started in January 2021, signifying an essential step toward understanding the effects of the medication on outpatients with early-diagnosed, symptomatic COVID-19, demonstrating how repurposing drugs may be an effective strategy in combatting the disease.
Dr Edward Mills, the co-principal investigator of the trial from McMaster University, said: “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.”
“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.”
What is fluvoxamine?
Fluvoxamine is a type of selective serotonin reuptake inhibitor (SSRI) that is traditionally employed to treat a range of mental health conditions, such as anxiety, depression, and obsessive-compulsive disorders and was selected as a potential COVID-19 treatment due to its anti-inflammatory qualities.
Dr Angela Reiersen, the study’s co-author and Associate Professor of Psychiatry at Washington University in St. Louis, said: “Fluvoxamine may reduce the production of inflammatory molecules called cytokines, that can be triggered by SARS-CoV-2 infection.”
Investigating repurposing potential
For their investigation, the researchers recruited a cohort of Brazilian adults who were symptomatic, tested positive for COVID-19, were unvaccinated, and had at least one additional criterion that made them high-risk. 741 of the participants were administered two 100mg doses of fluvoxamine daily for ten days, with a further 756 participants receiving a placebo.
The participants were subsequently observed for four weeks following the treatment. The main outcome of the trial was patients spending over six hours receiving physician treatment at a specialised COVID-19 emergency setting or hospitalisation. Of the patients who received fluvoxamine, 79 (10.6%) required this extended stay compared to the 119 (15.7%) who received the placebo.
The results of the study elucidate an absolute reduction in hospitalisations and prolonged emergency care, with an additional relative risk reduction of 32%. Despite mortality not being a primary outcome of the study, a secondary per-protocol analysis of patients who took 80% of the fluvoxamine doses revealed one death in the fluvoxamine group compared to 12 in the placebo.
Dr Gilmar Reis, a co-principal investigator, based in Belo Horizonte, Brazil, commented: “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.”
Study limitations
One of the limitations of the study is that although fluvoxamine is widely available, it is currently not on the World Health Organization’s Essential Medicine List. However, a closely related SSRI – called fluoxetine – is on the list, and the team believe it is vital to now investigate if these drugs can be used interchangeably to treat COVID-19.
The team also explained that these interventions with fluvoxamine and fluoxetine are highly dependent on identifying which patients are at the highest risk of deterioration from COVID-19 in the early stages of infection.
Otavio Berwanger of the Academic Research Organisation of Hospital Israelita Albert Einstein, who was not involved in the study, commented: “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, it 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.”
