A recent randomised clinical trial conducted under the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) programme has raised questions about the effectiveness of montelukast in reducing symptom duration in mild to moderate COVID-19 cases. The study, which ran from January 27 to June 23, 2023, across 104 U.S. sites, found no significant difference between montelukast and placebo in hastening the recovery of outpatients. The study has prompted a critical review of the role of montelukast in treating less severe COVID-19 cases.

The primary aim of the study was to assess whether montelukast, a leukotriene receptor antagonist often used to treat asthma, could reduce the duration of COVID-19 symptoms compared to a placebo in patients with mild to moderate cases. Participants were required to be at least 30 years old with confirmed SARS-CoV-2 infection and two or more acute symptoms for less than seven days.

A total of 1,250 participants were enrolled and randomised to receive either 10 mg of montelukast once daily or a placebo for 14 days. Among the 628 participants who received montelukast and 622 participants who received placebo, no significant difference was observed in the primary outcome—time to sustained recovery, defined as three consecutive days without symptoms. The trial's secondary outcomes included hospitalisation, healthcare utilisation events, and clinical progression, none of which showed notable differences between the two groups.

The results of the trial indicate that montelukast is no more effective than a placebo in reducing the duration of symptoms in mild to moderate COVID-19 cases. The unadjusted median time to sustained recovery was 10 days in both groups, and no deaths were reported. Hospitalizations were minimal, with only two participants from each group requiring hospital care. The healthcare utilisation event rate remained identical between the two groups at 2.9%.

The researchers concluded, "In this randomised clinical trial of 1,250 adults with mild to moderate COVID-19, montelukast, 10 mg daily for 14 days, did not improve time to sustained recovery compared with placebo." This finding raises significant doubts about the drug's efficacy in treating less severe cases of COVID-19, despite earlier studies suggesting possible benefits in more severe cases.

Several previous studies have pointed to potential benefits of montelukast in treating hospitalised COVID-19 patients, but these studies had design limitations. In one open-label trial involving 180 hospitalised patients with moderate to severe COVID-19, montelukast combined with gabapentin was found to reduce the frequency and severity of cough compared to gabapentin alone. However, the group treated with dextromethorphan, a cough suppressant, experienced better outcomes than either experimental group.

Another study involving 180 hospitalised COVID-19 patients found that higher doses of montelukast (20 mg daily) significantly reduced inflammatory markers and improved pulmonary function. However, the trial was limited by a lack of significant clinical events to compare between groups.

A third retrospective study involving 92 hospitalised patients showed fewer clinical deterioration events in those receiving montelukast compared to those who did not. Despite these findings, the ACTIV-6 trial results highlight a stark difference between the effects of montelukast in more severe COVID-19 cases versus mild to moderate cases. As the researchers noted, "It is possible that these three studies found a potential benefit from montelukast for more severe COVID-19, while the ACTIV-6 trial did not find a benefit in patients with less severe disease."

The ACTIV-6 trial casts doubt on the utility of montelukast for outpatients with mild to moderate COVID-19, suggesting that its benefits may be limited to more severe cases. These findings have important implications for clinicians managing COVID-19 patients in outpatient settings. While montelukast may offer some therapeutic advantages in hospital settings, particularly for more severe disease, its role in treating less severe cases remains unproven.

As the world continues to grapple with the management of COVID-19, the study underscores the importance of critically assessing existing therapies and exploring new treatments tailored to disease severity. The researchers emphasised that more studies are needed to fully understand montelukast’s potential role in COVID-19 care, particularly in relation to more severe cases where inflammatory responses are heightened.