A recent clinical trial has found that montelukast, a common asthma medication, does not shorten the recovery time for outpatients experiencing mild to moderate COVID-19. The study, part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform, involved 1,250 participants across 104 sites in the United States and was conducted between January and June 2023, a period dominated by SARS-CoV-2 Omicron subvariants. The findings, published in JAMA Network Open, indicate that montelukast is not an effective treatment for reducing the duration of COVID-19 symptoms in this patient population.
The ACTIV-6 study, a decentralized, double-blind, placebo-controlled trial, aimed to evaluate the efficacy of repurposed medications for outpatient COVID-19 treatment. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and at least two acute COVID-19 symptoms for less than seven days were enrolled. They were randomized to receive either montelukast (10 mg daily) or a matching placebo for 14 days. The primary outcome was the time to sustained recovery, defined as three or more consecutive days without symptoms.
The results showed no significant difference in the time to sustained recovery between the montelukast and placebo groups. The median time to recovery was 10 days in both groups (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92 to 1.12; P = .63 for efficacy). Secondary outcomes, including time to death, hospitalization, or healthcare utilization, also showed no significant differences. No deaths occurred in either group, and hospitalizations were reported for two participants (0.3%) in each group.
Detailed Findings
On the first day of the study, only 3.7% of participants reported no symptoms, while 33.2% reported mild symptoms, and 61.0% reported moderate symptoms. Participants were enrolled within a median of 4 days of symptom onset and received montelukast or placebo within a median of 5 days. Over half of the participants (56.3%) reported receiving at least two doses of a COVID-19 vaccine.
Researchers noted that montelukast has anti-inflammatory effects and has shown potential antiviral activity against SARS-CoV-2 in in vitro studies. However, the clinical trial results did not support these findings in the context of mild to moderate COVID-19.
Expert Commentary
Russell Rothman, MD, MPP, the Ingram Professor of Integrative and Population Health and Senior Vice President of Population and Public Health at VUMC, stated, "This randomized trial has demonstrated that montelukast does not appear to be helpful in treating COVID-19 in the outpatient setting."
Christopher Lindsell, PhD, professor and co-chief of the Division of Biostatistics and Bioinformatics at Duke University School of Medicine and director of DCRI Data Science and Biostatistics, emphasized the importance of negative results, saying, "Knowing that a treatment doesn’t work is as crucial as knowing it does. It prevents unnecessary use and potential harm."
Implications for COVID-19 Treatment
The study's findings contribute to the growing body of evidence regarding potential treatments for COVID-19. While several antiviral drugs have been developed for hospitalized patients, effective therapies for those with milder symptoms remain limited. The ACTIV-6 platform continues to evaluate other repurposed medications in the hope of identifying effective outpatient treatments.
Trial Limitations
The study authors noted several limitations, including the relatively low number of clinical events observed, which limited the ability to evaluate the treatment effect of montelukast on relevant clinical outcomes. Additionally, the decentralized trial approach introduced a delay between enrollment and receipt of the study drug, which could be significant for a proposed antiviral mechanism of action. The median time from symptom onset to receiving the study drug was 5 days, with 90.2% of patients receiving it within 7 days.
Conclusion
The ACTIV-6 trial demonstrated that montelukast does not improve the time to sustained recovery in outpatient adults with mild to moderate COVID-19. These findings do not support the use of montelukast for this indication. Further research is needed to identify effective and accessible treatments for managing COVID-19 in the outpatient setting.
