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The extensive quest to repurpose a cheap therapy for non-hospitalized COVID patients has once again fallen short, this time using a higher dose of fluvoxamine (Luvox), a selective serotonin reuptake inhibitor (SSRI).

In the latest readout from the multi-platform ACTIV-6 trial, time to sustained recovery landed at an identical 10 days whether patients with mild to moderate cases received a 100-mg twice-daily dose of the SSRI or placebo (adjusted HR 0.99, 95% credible interval [CrI] 0.89-1.09, P=0.40), reported Susanna Naggie, MD, MHS, of Duke University School of Medicine in Durham, North Carolina, and colleagues in .

Numbers for hospital admissions and visits to the emergency department or urgent care trended lower in the fluvoxamine group, at 2.4% versus 3.6% with placebo, but that difference was not significant (HR 0.69, 95% CrI 0.27-1.21, P=0.86); no deaths occurred in either arm.

The new study -- which involved a highly vaccinated patient population -- adds to the mixed findings reported to date for fluvoxamine in COVID-19, with positive findings from the TOGETHER trials when used either alone or , and negative results from the and COVID-OUT trials. Prior results from ACTIV-6 testing a lower dose of fluvoxamine also failed to speed recovery time in outpatients.

"The evolution of the pandemic, with changes in the severity of COVID-19 over time and increasing infection-related and/or vaccine-induced immunity, suggests that the circumstances of the present study are meaningfully different than those of earlier trials," Naggie and co-authors wrote.

Given the decreasing rates of serious COVID outcomes amid greater population immunity, "future trials may need to focus on composite outcomes such as healthcare utilization or enroll a larger number of participants to conclusively understand the impact of any therapeutic agent on outcomes," they added.

Of note, the FDA last year rejected an effort by researchers requesting emergency use authorization for fluvoxamine as a treatment for mild to moderate COVID-19.

"The ACTIV platform was not first to the finish with practice-changing evidence for patients hospitalized with COVID-19," noted authors of an . That distinction goes to the RECOVERY platform trial from the U.K., which showed a survival benefit with dexamethasone and harm with hydroxychloroquine in hospitalized patients.

"However, the ACTIV platform also quickly began generating key insights for outpatient management of COVID-19 infection, such as the ineffectiveness of ivermectin," wrote JAMA deputy editors Joseph S. Ross, MD, MHS, of Yale School of Medicine in New Haven, Connecticut, and Preeti Malani, MD, MSJ, of the University of Michigan Medical School in Ann Arbor.

Data analysis for the present study included 1,208 randomized participants who within 7 days of COVID symptom onset received fluvoxamine (50 mg twice-daily on the first day followed by 100 mg twice-daily for 12 more days) or placebo. The study's primary outcome of sustained recovery was defined as 3 straight days without symptoms.

Patients ages 30 and older were enrolled from August 2022 to January 2023 at over 100 U.S. sites, and they needed to have a confirmed infection with at least two symptoms.

Participants had a median age of 50 years, and about two-thirds were women. Upwards of 70% of the study population were white, 9% were Black, and 46% identified as Hispanic. More than three-fourths had received at least two doses of COVID vaccine. About a fourth had hypertension, 14% had asthma, 13% had diabetes, and 6% had heart disease.

A total of 35 healthcare events occurred (hospitalizations, emergency department visits, urgent care clinic visits), with 14 in the study arm and 21 in the placebo arm. One hospitalization occurred among the fluvoxamine group, with two in the placebo group.

As for safety, seven serious adverse events were reported among six of the outpatients: two in the SSRI group and four in the placebo group.

Naggie and co-authors did note some limitations to their randomized trial, including the few clinical events that prevented more detailed analysis of the secondary outcomes, along with some delays in access to the study drug as it had to be mailed out (arriving a median 2 days from symptom onset).

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