The TOGETHER Randomized Clinical Trials Shows That Fluvoxamine Reduces Risk Of COVID-19 Disease Severity And Reduces Need For Hospitalization
: The results from the TOGTHER clinical trial has shown that fluvoxamine reduces the risk of COVID-19 disease severity and reduces the need for hospitalization.
The TOGETHER trial is a randomized, adaptive platform trial to investigate the efficacy of repurposed treatments for COVID-19 disease among high-risk adult outpatients. 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),10 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).
This arm of the TOGETHER trial is the largest randomized trial to date to assess the effectiveness of fluvoxamine for patients with COVID-19 in the community.
The trial findings showed that treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalization defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.
Numerous emerging evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, the study team aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalization defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.
This placebo-controlled, randomized, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation.
The primary outcome was a composite endpoint of hospitalization defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high-level adherence (>80%). The team used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing.
study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization 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 tertiary 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 hospitalizations. 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). The study team found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups.
The trial results published in the peer reviewed journal: 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 or hospitalization, compared to a control group who received a placebo. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext
The trial 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.
Co-principal investigator Dr Edward Mills of McMaster University-Canada told Thailand Medical News, “Despite the fact that 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, the disease still poses a risk to individuals in countries with low resources and limited access to vaccinations. Hence 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."
Dr Angela Reiersen, Associate Professor of Psychiatry at Washington University in St. Louis and co-author added,” 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. Fluvoxamine may reduce the production of inflammatory molecules called cytokines, that can be triggered by SARS-CoV-2 infection."
The ongoing TOGETHER trial is a randomized 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.
In all, a total of 741 participants were given 100mg of fluvoxamine twice daily for ten days and another 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 specialized COVID-19 emergency setting, or hospitalization.
Interestingly, 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 hospitalization, compared to 119 out of the 756 (119/756 [15.7%]) participants who received the placebo.
The study findings demonstrated an absolute reduction in the risk of prolonged hospitalization/prolonged emergency care of 5% with and a relative risk reduction of 32%.
While 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.
Dr Gilmar Reis, co-principal investigator, based in Belo Horizonte, Brazil added,"Our clinical trial 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."
The study team acknowledges 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.
Also, the study team notes that the use of interventions, including fluvoxamine, to prevent progression of illness and hospitalization is critically dependent on reliably identifying individuals at highest risk of deterioration in the early stages of COVID-19 infection.
Dr Otavio Berwanger of the Academic Research Organization of Hospital Israelita Albert Einstein, Sao Paulo, Brazil, who was not involved in the study, commented in an accompanying review in the journal, "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 hospitalizations 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."
Thailand Medical News suggest readers also access the following articles to know more about fluvoxamine and COVID-19: https://www.thailandmedical.news/news/breaking-fluvoxamine-an-inexpensive-anti-depressant-emerging-as-a-leading-drug-candidate-to-be-repurposed-to-treat-covid-19
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