Montelukast Does Not Shorten Duration of Symptoms in Patients With Mild-to-Moderate COVID-19

In a randomized clinical trial of patients with mild-to-moderate COVID-19 (NCT04885530), montelukast (Singulair; Organon) did not reduce duration of symptoms associated with infection, with the investigators deeming it ineffective as a potential treatment of COVID-19, according to results published in the Journal of the American Medical Association.^1,2

COVID-19 can involve an increase in cytokines, leading to worse clinical outcomes. | Image Credit: © sdecoret | stock.adobe.com

Montelukast is an orally active leukotriene receptor antagonist with anti-inflammatory properties that was previously approved to treat asthma. A research analysis published in Drug Discovery Today examined the effects that montelukast could have on patients with COVID-19, the virus caused by SARS-CoV-2, given its known suppressive effects on oxidative stress and cytokine production. The reviewers suggested that repurposing montelukast could reduce the severity of COVID-19 symptoms.^1,3

Though prior clinical studies of hospitalized patients with COVID-19 have suggested a potential benefit with montelukast, the trials had small numbers of enrolled patients and other significant limitations. Further, no clinical trials had assessed the role of montelukast in outpatients with COVID-19, until the initiation of the Accelerating Coronavirus Disease 2019 Therapeutics Interventions and Vaccines (ACTIV-6) trial.¹

In that trial, repurposed medications in the outpatient setting were administered to patients to determine their effectiveness in reducing COVID-19 symptoms. Montelukast was evaluated for the effect on time to a sustained recovery from symptoms in non-hospitalized adults with mild-to-moderate COVID-19.¹

A total of 1453 patients were enrolled in the montelukast arm, of which 1250 were included in the modified intention-to-treat (MITT) cohort. Of these patients, 628 were assigned to receive montelukast while 622 were matched to placebo. Importantly, 704 (56.3%) participants reported receiving at least 2 doses of a SARS-CoV-2 vaccine, with 153 (12.2%) reporting that they had received a COVID-19 therapy in the past.¹

There were no differences in time to sustained recovery observed in both the unadjusted Kaplan-Meier curves or covariate-adjusted regression models. In both the montelukast and placebo groups, median time to sustained recovery was 10 days (95% CI, 10-11 days). In each study group, 2 participants were hospitalized, and 18 participants (2.9%) in either group reported hospital admission, emergency department or urgent care visits, or death.¹

As mentioned previously, other clinical trial results have suggested a positive treatment benefit from montelukast for inpatients with COVID-19. One such trial, conducted by Kerget et al, evaluated 2 different montelukast doses—10 mg daily or 20 mg daily—compared with standard of care alone in 180 hospitalized patients.⁴

The investigators of that trial did find that inflammatory markers were significantly lower in the montelukast group at day 5 compared with the standard of care group. However, the results showed that only the higher-dose montelukast group had improved their pulmonary function testing, which is not feasible for many patients.⁴

Although the results of the current study indicate the ineffectiveness of montelukast, this trial too has limitations that could affect the results. Few clinical events were observed in the trial, possibly due to the nature of the pandemic at the time. Additionally, the decentralized approach to the trial limited the ability to send the study drug through a courier, which could be significant for determining antiviral mechanism of action.¹

REFERENCES

1. Rothman RL, Stewart TG, Mourad A, et al. Time to sustained recovery among outpatients with COVID-19 receiving montelukast vs placebo: The ACTIV-6 randomized clinical trial. JAMA Netw Open. 2024;7(10):e2439332

2. ClinicalTrials.gov. ACTIV-6: COVID-19 study of repurposed medications. National Library of Medicine. Updated June 12, 2024. Accessed October 21, 2024. https://clinicaltrials.gov/study/NCT04885530

3. Sanghai N, Tranmer GK. Taming the cytokine storm: repurposing montelukast for the attenuation and prophylaxis of severe COVID-19 symptoms. Drug Discovery Today. 2020;25(12):2076-2079. doi:10.1016/j.drudis.2020.09.013

4. Kerget B, Kerget F, Aydin M, et al. Effect of montelukast therapy on clinical course, pulmonary function, and mortality in patients with COVID-19. Medical Virology. 2022;94(5):1950-1958. doi:10.1002/jmv.27552