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Adults with mild to moderate COVID-19 treated with 50 mg of fluvoxamine (Luvox) twice daily for 10 days did not recover more quickly than those taking placebo, the ACTIV-6 randomized controlled platform trial showed.

Among nearly 1,300 adult outpatients, sustained recovery with no symptoms for at least 3 days in a row took a median of 12 days for those treated with fluvoxamine versus 13 days for those on placebo (HR 0.96, 95% CI 0.86-1.06, P=0.21).

The secondary outcome of a composite of requiring hospital, urgent care, or emergency department care was also similar between treatment and control groups (26 vs 23 cases, 3.9% vs 3.8%), found Susanna Naggie, MD, of Duke University School of Medicine in Durham, North Carolina, and colleagues.

"These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19," the researchers reported in . However, "there are numerous conflicting trials for the use of fluvoxamine, and some of the differences may be attributable to dosage."

They cited the TOGETHER trial, in which treating mild COVID-19 in high-risk patients with a 100 mg dose of fluvoxamine twice daily -- twice the amount given to ACTIV-6 participants -- reduced hospitalization. However, "tolerability has been identified as a potential limiting factor for use of this dose of fluvoxamine," Naggie and her colleagues noted.

But despite early trials suggesting benefit for all-cause hospitalization, and did not confirm those benefits.

Preliminary results of the ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) trial, presented at IDWeek in October, did not show benefit for any repurposed drugs, including ivermectin, metformin, or fluvoxamine for the treatment of COVID-19.

Precisely when these trials were done, the predominant variants circulating at the time, baseline risk in the populations studied, and vaccination status were all likely to have influenced interpretation of these and earlier trials, according to an by Adarsh Bhimraj, MD, of Houston Methodist Hospital, and Jason C. Gallagher, PharmD, of Temple University in Philadelphia.

Fluvoxamine was "one of the more interesting" therapeutic candidates identified in the "scramble to investigate approved medications for repurposing against SARS-CoV-2," they noted, since this inexpensive, generic selective serotonin reuptake inhibitor has putative anti-SARS-CoV-2, anti-inflammatory, and antiplatelet activity.

While the between-trial difference in dosing regimens could have been a factor in the different trial results, the editorialists concluded that "the totality of evidence for fluvoxamine does not support its current use for treatment of mild to moderate COVID-19."

In May, the FDA rejected an emergency use authorization application for the use of fluvoxamine to treat COVID-19, calling the available data insufficient.

While crediting the researchers of the fluvoxamine studies "for their persistence in investigating the possible role of this inexpensive therapy," Bhimraj and Gallagher wrote that the same is needed for other drugs, such as authorized antivirals. "Drugs shown to be effective earlier in immune-naive populations and against more problematic SARS-CoV-2 variants require further study to define their role in the current landscape of COVID-19."

The fluvoxamine trial within ACTIV-6 included 1,288 outpatients ages 30 or older (median 47 to 48) with confirmed SARS-CoV-2 infection for 10 days or less and two or more COVID-19 symptoms for 7 days or less.

The study population was evenly matched with controls. About two-thirds of participants had received two or more doses of COVID-19 vaccine; women represented 57% of the study population. In total, 2.3% in both the treatment and control groups presented with severe symptoms on day 1.

Treatment and control groups reported similar rates of hypertension (23.3% vs 25.7%), asthma (13.5% vs 12.8%), diabetes (9% vs 9.5%), and heart disease (3.5% vs 5.1%).

One person was hospitalized in the treatment group and two were in the placebo group. There were no deaths reported in either group during the 28-day follow-up.

The study was limited by the few clinical events and inability to study clinical outcomes. Further, the median time to start study medication was 5 days following symptom onset, "which is at the upper limit of the recommend start of antiviral medicines," the researchers noted.

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