Long-Acting Muscarinic Antagonist as an Alternative to Inhaled Corticosteroids in Type 2-Low Mild Asthma: A Randomized Crossover Non-inferiority Trial.

Abstract

Type 2 (T2)-low asthma is often less responsive to inhaled corticosteroids (ICS); however, optimal controller strategies for this phenotype remain inadequately defined. To evaluate whether long-acting muscarinic antagonists (LAMA) are non-inferior to ICS in patients with T2-low mild asthma. In this multicenter, pragmatic, randomized, open-label, crossover trial, adults with T2-low mild asthma (blood eosinophils <300/μL, and either FeNO <25 ppb or sputum eosinophils <3%) were randomized 1:1 to 6 months of ICS followed by 6 months of LAMA, or vice versa. The primary outcome was a composite treatment-success endpoint. Non-inferiority was established if the lower bound of the 95% confidence interval (CI) for the success rate difference was greater than -10 percentage points. Among 150 randomized patients, 89 completed both phases (per-protocol population). Treatment success was 7.9 percentage points higher with LAMA (95% CI, -2.9 to 18.8; P<0.001), consistent with two intention-to-treat analyses (risk differences, 4.1-4.2 percentage points). In another intention-to-treat analysis where all uncompleted phases were considered as failures, non-inferiority was not established (-3.3 percentage points; 95% CI, -11.3 to 4.5), though it was supported under a non-responder imputation approach for missing data (one-sided P = 0.020). The favorable effect was more pronounced in patients aged <65 years. Exacerbation rates did not differ significantly, and symptom control and lung function remained stable across both phases. In patients with T2-low mild asthma, LAMA monotherapy may be non-inferior to ICS and may be considered an alternative controller option for selected patients.