In a recent study published in the Journal of American Medical Association, researchers investigate the effects of high-dose fluvoxamine among patients with mild-to-moderate coronavirus disease 2019 (COVID-19).
Study: Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial. Image Credit: Scout Chaplin-Loebell / Shutterstock.com
Evidence supporting fluvoxamine for COVID-19 treatment
Multiple clinical trials have investigated approved drugs as repurposed therapies for patients with mild-to-moderate COVID-19. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) proposed to reduce inflammatory responses and prevent severe disease progression. Although one study suggested that fluvoxamine decreased hospitalization rates in adult patients, this evidence was insufficient to recommend its use.
Taking 100 mg of fluvoxamine two to three times each day has been shown to reduce emergency room visits and hospitalization; however, tolerability has been a limitation. To overcome this challenge, a lower dose of 50 mg has been shown to improve tolerability; however, this dose was ineffective in two clinical trials.
The accelerating COVID-19 therapeutic interventions and vaccines (ACTIV-6) platform clinical trial evaluates repurposed drugs. In an ACTIV-6 trial involving over 1,300 adult COVID-19 patients randomized to 50 mg fluvoxamine or placebo, there were no differences in the time to sustained recovery between groups.
The lack of effectiveness of fluvoxamine in this trial was likely due to the inadequate dose. Nevertheless, the conflicting findings from large trials warrant validation of the therapeutic benefits of fluvoxamine at a higher dose.
About the study
In the present study, researchers evaluate the effects of a higher dose of fluvoxamine in mild-to-moderate COVID-19 patients. Eligible subjects were aged 30 or older with a positive antigen or polymerase chain reaction (PCR) test result. Furthermore, each study participant reported experiencing at least two of the following symptoms including sore throat, loss of sense of smell/taste, body aches, diarrhea, vomiting, cough, nausea, dyspnea, fatigue, nasal symptoms, fever, and chills.
Participants were recruited from August 25, 2022, to January 20, 2023. Subjects were excluded if they participated in other COVID-19 trials, were pregnant, breastfeeding, recently/currently hospitalized for COVID-19, using fluvoxamine, or had bipolar disorder or contraindications/allergy to fluvoxamine.
Participants were instructed to consume two 50 mg tablets of fluvoxamine or placebo on the first day and 100 mg tablets of fluvoxamine or placebo twice a day for the next 12 days. Medical history, demographic information, race/ethnicity, COVID-19 symptoms, and use of other medications were self-reported by the participants.
The primary outcome was the time to sustained recovery, which was defined as the time from intervention to the third of three consecutive days without symptoms. Secondary outcomes included time to hospitalization/death, time to death, COVID-19 clinical progression scale scores, average time spent unwell, and a composite of emergency room/urgent care visits, hospitalization, or death.
The study randomized 1,175 participants to receive fluvoxamine or placebo. About 66% of the study participants were female and 72.7% were White. Hypertension and obesity were the most common comorbidities.
Over 75% of participants received at least two doses of a COVID-19 vaccine. About 10% of participants reported no symptoms at the time of study drug receipt, whereas the remainder reported mild/moderate symptoms.
There were no differences in time to sustained recovery between groups, with a median of 10 days. No deaths occurred in either group. Three participants were hospitalized, including one fluvoxamine recipient.
Fourteen fluvoxamine recipients and 21 placebo recipients reported emergency room/urgent care visits or hospital admission. The clinical progression scale was simplified into a self-evaluation of home activity levels, as hospitalizations and deaths were rare.
Over 95% of study participants had no activity limitations by day seven. Moreover, the average time spent unwell was similar between groups.
Six individuals experienced serious adverse events. More specifically, two fluvoxamine recipients reported Guillain-Barre syndrome, pneumonia, and aggravated asthma, whereas four placebo recipients reported perforated intestinal diverticulitis, partial bowel obstruction, ruptured appendix, and diabetic foot ulcer.
The researchers did not observe a meaningful separation between groups when stratified by symptom severity at baseline and timing of therapy relative to symptom onset. Exploratory analyses suggested that participants who received fluvoxamine more quickly following the onset of their symptoms had poorer symptom resolution than placebo recipients. In contrast, those who received fluvoxamine treatment around seven days post-symptom onset had better resolution than placebo participants.
The study findings indicate that treating mild-to-moderate COVID-19 patients with a higher dose of fluvoxamine did not improve the primary outcome relative to placebo recipients. Notably, the secondary composite outcome of healthcare utilization or death suggested nearly 33% fewer events among fluvoxamine recipients; however, this effect did not meet decision-making thresholds.