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Among patients with mild to moderate COVID-19, the asthma drug montelukast (Singulair) did not reduce duration of symptoms, results of the randomized controlled ACTIV-6 trial showed.

After receiving montelukast or placebo for 14 days, no differences in time to sustained recovery were observed between groups (adjusted HR 1.02, 95% credible interval 0.92-1.12, P=0.63), and the unadjusted median time to sustained recovery was 10 days for both groups, reported Susanna Naggie, MD, MHS, of the Duke University School of Medicine in Durham, North Carolina, and colleagues in .

"In this case, across the entire population of the study, we did not see a clear benefit," Naggie told MedPage Today. "So I think there are a lot of people who were interested in montelukast as a potential active drug, and I think this says that at least in the overall population, that's not true, but that maybe there are some populations where further study would be justifiable."

She noted that "there was maybe a hint" that getting the drug earlier in the disease course may have been beneficial, but "that has not been true of most of the other drugs that we've studied," and further studies should investigate this question specifically.

Naggie said she and her team had a "twofold" hypothesis: that montelukast might address both the viral and inflammatory phases of COVID-19. As an antiviral, some in vitro studies suggested the drug could inhibit some of the enzymes necessary for SARS-CoV-2 to replicate. And in its use for asthma and allergic rhinitis, the drug blocks several receptors in pro-inflammatory pathways in the body, acting as an anti-inflammatory.

However, Naggie added that because the disease has gotten milder, "I think over time, it's gotten harder and harder to be able to find a difference between groups who get the active drug and groups who don't. So we knew that going in, right? You'd have to find a drug that was highly, highly effective, and we did not see that."

In an , John O'Horo, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, noted that it can be relatively easy to demonstrate the benefit of a proposed therapeutic in a critically ill population, but in this study population, events like hospitalizations or deaths were rare.

"The safety profile needed for mild outpatient therapy is substantially more conservative and makes finding a cost-effective therapeutic more challenging," O'Horo pointed out.

"Montelukast can now be added to the list of failed therapeutics, but the importance of even negative results in this space cannot be overstated," he wrote. "All therapeutics come with potential harms and knowing that the risks outweigh putative benefits is crucial as outpatient management of COVID-19 becomes more important."

This study was part of (Accelerating COVID-19 Therapeutic Interventions and Vaccines), an ongoing platform trial program evaluating repurposed medications for mild to moderate COVID-19. It allowed patients to participate remotely, and the montelukast arm ran from January through June 2023 during circulation of Omicron subvariants. Eligible participants were age 30 and older, with confirmed SARS-CoV-2 infection and two or more acute COVID-19 symptoms for less than 7 days.

Patients with current or recent COVID-19 hospitalization, participation in other COVID-19 trials, or sensitivity or allergy to montelukast were excluded. COVID-19 vaccinations or current use of approved or emergency use authorization COVID-19 outpatient treatments were allowed.

In total, 1,250 participants across 104 sites were randomized into the placebo or montelukast groups. The median age was 53 years, 60.2% were women, 78.2% were white, and 56.3% reported having received two or more doses of a SARS-CoV-2 vaccine. They received montelukast 10 mg or placebo once daily for 14 days. Patients had doses delivered by a pharmacy, and took them orally.

Secondary outcomes included time to death; time to hospitalization or death; a composite of healthcare utilization events including hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell.

No deaths occurred, and two participants in each group were hospitalized. There were no differences between groups in the composite of healthcare utilization events. Five participants had serious adverse events -- three in the montelukast group and two in the placebo group.

Study limitations included few observed clinical events due to increased population-level immunity to COVID-19, evolving viral variants over time, and the characteristics of the enrolled patients. In addition, sending the study drug through the mail introduced a delay between enrollment and receipt of the drug, a median of 5 days, which "might be significant for a proposed antiviral mechanism of action," the authors wrote.

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