Reference: JAMA. 2020 Dec 8;324(22):2292-2300
As we wrap up 2020 in the midst of this global pandemic, studies examining therapeutic options for non-hospitalized patients with COVID-19 remain limited. Selective serotonin reuptake inhibitors (SSRIs) are potential candidates for drug repurposing due to their safety profile, tolerability, low cost, and widespread availability. It’s hypothesized that SSRIs may be useful in the treatment of COVID-19 because they act as agonists on sigma-1 receptors (S1R), which regulate cytokine production. A recent trial examines the potential for fluvoxamine, an SSRI used primarily for the treatment of obsessive-compulsive disorder, to prevent clinical deterioration in patients who present with mild symptomatic COVID-19 and are able to remain at home. Investigators chose fluvoxamine because it has a particularly high affinity to S1R and preclinical data suggest that it protects mice from septic shock.
This study randomized 181 adults with recent-onset SARS-CoV-2 infection to either fluvoxamine or placebo for 15 days. Symptomatic patients were eligible if they had ≤ 7 days of symptoms, oxygen saturation ≥ 92%, and did not require hospitalization. In typical 2020 fashion, researchers pulled off this study entirely remotely. Participants were mailed the study medication and equipment for self-assessment (pulse oximeter, automated blood pressure cuff, and thermometer). Fluvoxamine dosing was titrated from 50 mg on day one to 100 mg twice daily on day two to 100 mg three times daily on days 3-15. Vital signs, medication adherence, and symptoms were recorded by participants with twice-daily online surveys with phone calls as backup. Participants, research staff, and outcome assessors were blinded to treatment assignment. The primary endpoint was clinical deterioration within 15 days. Clinical deterioration was defined as dyspnea, hospitalization for shortness of breath, pneumonia plus oxygen saturation
< 92%, or need for supplemental oxygen to maintain oxygen saturation ≥ 92%. Out of 181 randomized adults, 152 adults (mean age 46 years, 72% women) received study medication and 115 completed the 15-day assessment. Clinical deterioration within 15 days occurred in 0 of 80 patients in the fluvoxamine group vs. 6 of 72 in the placebo group (p = 0.009, NNT 12). Four patients in the placebo group were hospitalized and one required mechanical ventilation.
At first glance, the asymmetric prevention of deterioration may seem impressive, but we aren’t ready to start prescribing fluvoxamine to all outpatients with COVID. There are methodological concerns with this trial, including a high dropout rate, short-term follow-up, and differences between the two groups in baseline oxygen saturation distributions. The placebo group had lower oxygen saturation levels at the trial outset, which could indicate that this group was sicker to begin with and potentially more likely to clinically deteriorate. To be fair, this fully remote trial was quite the undertaking. However, the results need to be confirmed in a larger trial or they may end up falling into the wastebasket of the replication crisis as we have seen with many other COVID treatments.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Faculty Development Fellow and Clinical Instructor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor of Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed; and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia.