A 14-day course of the oral anti-inflammatory drug montelukast didn't shorten symptom duration in nonhospitalized US adults with mild or moderate COVID-19, finds a randomized controlled clinical trial published today in JAMA Network Open.

 

The Accelerating COVID-19 Therapeutic Interventions and Vaccines-6 (ACTIV-6) Study Group and Investigators randomly assigned 1,250 infected participants aged 30 and older to receive a 14-day course of montelukast (10 milligrams daily) or placebo from January 27 to June 23, 2023, a period dominated by SARS-CoV-2 omicron subvariants. The ongoing ACTIV-6 platform trial assesses repurposed drugs for COVID-19 outpatients.

 

Drug given within five days

 

On day one of the study, 3.7%, 33.2%, and 61.0% of participants reported no, mild, or moderate symptoms, respectively. They were enrolled within a median of four days of symptom onset and received montelukast or placebo within a median of five days.

 

The matched participants were enrolled at 140 sites across the country. The median age was 53 years, 60.2% were women, and 56.3% reported receiving at least two doses of COVID-19 vaccine.

 

"Montelukast, an orally active leukotriene receptor antagonist with anti-inflammatory effects, has been shown to suppress oxidative stress and cytokine production," the researchers wrote.

 

"While montelukast is currently approved for the treatment of asthma and allergic rhinitis, in silico screening (based on in vitro studies for other RNA viruses) supports the plausibility of antiviral activity through inhibition of SARS-CoV-2 protease and polymerase enzymes."

 

10-day median time to symptom resolution

 

Time to sustained recovery, defined as three or more days without symptoms, didn't differ between the 628 and 622 participants assigned to montelukast or placebo, respectively (adjusted hazard ratio [aHR], 1.02; 95% credible interval [CrI], 0.92 to 1.12). The unadjusted median time to symptom resolution was 10 days in both groups.

 

By day 7, 89.8% of patients in the montelukast group and 89.6% of placebo recipients reported no limitations in activity and thus didn't meet the prespecified thresholds for a beneficial treatment effect (OR, 1.31; 95% CrI, 0.50 to 2.29). Likewise, the difference in average symptom duration was similar between the montelukast and placebo groups (11.8 vs. 12.0 days; difference, −0.24 days).

 

Eighteen participants (2.9%) in each group sought medical care, two (0.3%) in each group were hospitalized, and five (0.4%) and three (0.5%) in the montelukast and placebo groups, respectively, experienced serious adverse events. The events in the montelukast group were pneumonia, lower-extremity cellulitis, and ovarian torsion. The placebo-group events were pneumonia and acute appendicitis. No deaths were reported (aHR, 1.01; 95% CrI, 0.45 to 1.84).

 

Analyses of a priori–defined characteristics found that as time from symptom onset to montelukast receipt increased beyond 9 days, the treatment effect favored placebo, but the researchers noted that this represented only 28 participants. Likewise, the treatment effect in participants no longer reporting symptoms on study day one favored placebo, but this involved only 41 participants.

 

"These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19," the study authors concluded.

 

Challenges of testing drug in non-severe infections

 

In a related commentary, John O'Horo, MD, MPH, of Mayo Clinic, noted the challenges of assessing the effect of a drug in patients with mild or moderate COVID-19.

 

"Early in the pandemic, when hospitalizations trended toward more severe illness, it was comparatively easy to demonstrate a benefit of a proposed therapeutic and balance it against harms in a critically ill population," he wrote. "The safety profile needed for mild outpatient therapy is substantially more conservative and makes finding a cost-effective therapeutic more challenging."

 

Currently available options for non-severe COVID-19 are expensive and limited, O'Horo said. "Remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir have all shown some efficacy in reducing disease progression, although the magnitude of those benefits is now being brought into question, and the cost of these therapeutics is high," he wrote. "Monoclonal antibodies are no longer available, and the indications for convalescent plasma have been shrinking."

 

While montelukast has been ruled out as a candidate for the treatment of mild or moderate COVID-19, O'Horo said the search must go on. "Until a new option becomes available, we will all have to hold our breath," he concluded.