By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A randomized, placebo-controlled clinical trial found fluvoxamine (100 mg twice a day for 10 days) reduced the risk for hospitalization among high-risk outpatients diagnosed with COVID-19.

SOURCE: Reis G, Dos Santos Moreira-Silva EA, Medeiros Silva DC, et al. Effect of early treatment with fluvoxamine on the risk of emergency care and hospitalisation among patients with COVID-19: The TOGETHER randomized, platform clinical trial. Lancet Glob Health 2021; Oct. 27;S2214-109X(21)00448-4. [Online ahead of print].

Despite the widespread availability of COVID-19 vaccines, effective treatments that prevent or delay the progression of COVID-19 illness are urgently needed. Ideally, novel therapies should be oral, inexpensive, widely available, and have a low risk of adverse events. There is some evidence that fluvoxamine, an oral selective serotonin reuptake inhibitor used to treat depression, may reduce the risk for hospitalization due to COVID-19.1 Reis and colleagues, therefore, sought to determine the efficacy of fluvoxamine vs. placebo in preventing hospitalization among outpatients with an early diagnosis of COVID-19.

The study was a randomized, platform, placebo-controlled clinical trial conducted in 11 cities in Brazil. Patients included in the study were at least 18 years of age and presented to an outpatient care setting with an acute illness consistent with COVID-19. They must have had symptoms that started within seven days of the screening date or had a positive rapid test for SARS-CoV-2 antigen performed at the time of screening, or a positive SARS-CoV-2 diagnostic test within seven days of symptom onset. Patients also needed to have at least one additional criterion that put them at high risk for hospitalization, including diabetes mellitus, hypertension, cardiovascular disease, symptomatic lung disease, tobacco abuse, obesity, organ transplant recipient, chronic kidney disease (stage IV or on dialysis), immunosuppression or use of corticosteroid therapy equivalent to at least 10 mg of prednisone per day, history of malignancy in the preceding five years or actively undergoing cancer treatment, or being unvaccinated.

Patients were randomized 1:1 to receive either fluvoxamine 100 mg orally twice a day for 10 days or placebo. An electrocardiogram (ECG) was conducted at baseline for all participants. The primary endpoint was medical admission to a hospital for COVID-19 within 28 days of randomization.

There were 1,497 patients enrolled in the study, of which 741 were randomized to fluvoxamine and 756 to placebo. The median age was 50 years (range, 18-102 years) and 862 (58%) were female. The two groups were well balanced in terms of age, body mass index, and comorbidities. Hospitalization occurred in 79 of 741 (11%) of fluvoxamine recipients vs. 119 of 756 (16%) for those who received placebo; relative risk (RR), 0.68; 95% Bayesian credible interval (95% BCI): 0.52-0.88. Seventeen deaths occurred in the fluvoxamine group and 25 deaths occurred in the placebo group in the primary intention-to-treat analysis (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.36-1.27; P = 0.24). The number needed to treat was 20. Fluvoxamine was well tolerated and there were no significant differences in adverse events between those who received fluvoxamine vs. placebo.

COMMENTARY

The currently available treatments for COVID-19 (i.e., monoclonal antibodies and remdesivir) are given intravenously, so having an effective oral agent would be a game changer. Indeed, the oral direct-acting antiviral molnupiravir has generated considerable interest after it was shown to reduce the risk for hospitalization by 50% in those with early COVID-19.2 Reports indicate that a novel protease inhibitor, paxlovide, may have 89% efficacy bringing it to a level similar to that seen with monoclonal antibody therapy. However, other oral options remain an important goal. Since being approved by the Food and Drug Administration (FDA) in 1997, fluvoxamine has had a good safety record and generally is well tolerated. There now is growing evidence, as shown by the study from Reis et al and others, that fluvoxamine is an effective, safe, and relatively inexpensive treatment option for outpatients with mild COVID-19.The mechanism of action against SARS-CoV-2 is not well understood and needs further investigation. It may be due to anti-inflammatory properties, such as reducing platelet aggregation, decreasing mast cell degranulation, interfering with endolysosomal viral trafficking, regulating inositol-requiring enzyme 1α-driven inflammation, and increasing melatonin levels.3 Thus, there are likely to be other drugs used in clinical practice that can be similarly repurposed against COVID-19 that are waiting to be discovered.

The study by Reis et al was well-designed and is the largest randomized clinical trial to date to investigate the effect of fluvoxamine against COVID-19. However, there are a few limitations and unanswered questions worth mentioning. First, it is uncertain whether fluvoxamine will have the same efficacy against other strains of COVID-19, such as the Delta variant. Second, whether fluvoxamine can help those already hospitalized (e.g., prevent intensive care unit admission) is uncertain. Third, the study was conducted in one geographic area with a relatively homogeneous population, so the results might not be applicable to other regions and should be considered preliminary. Fourth, it is not known whether fluvoxamine is beneficial for vaccinated patients. Finally, the follow-up duration was relatively short and did not measure the effect of fluvoxamine on persistent symptoms (i.e., long COVID) or late deterioration.

The findings in this study are interesting and further support a role for fluvoxamine in the treatment of early COVID-19 in outpatients. Given the prevalence of vaccine hesitancy, an inexpensive oral drug that prevents hospitalizations, especially in the unvaccinated, could have important economic and public health benefits. 

REFERENCES

  1. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 2020;324:2292-2300.
  2. Mahase E. Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. BMJ 2021;375:n2422.
  3. Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme VV. Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Front Pharmacol 2021;12:652688.