A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study

Abstract

Background: Long-acting β2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma.

Methods: This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC).

Results: Abediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 μg had similar magnitude of peak FEV1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV1 AUC 0-6, 0-12, and 0-24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate.

Conclusions: Abediterol 0.625-2.5 μg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.

Figures

Figure 1

Diagram of patient flow.

Figure 2

Change from baseline in FEV1over time. Data are presented as least squares means with 95% confidence intervals: a) p < 0.0001 versus placebo for salbutamol and all doses of abediterol at all time points; b) p < 0.0001 for all doses of abediterol 0–24 h post-dose and abediterol 1.25 and 2.5 μg 36 h post-dose versus placebo, p = 0.002 and p = 0.01 for abediterol 0.313 and 0.625 μg, respectively, at 36 h post-dose versus placebo. FEV1, forced expiratory volume in 1 s.

Figure 3

Change from baseline in peak FEV1at Day 1. Data are presented as least squares means ± standard error: p < 0.0001 versus placebo for all doses of abediterol and salbutamol 400 μg; **p < 0.01, ***p < 0.001, ****p < 0.0001 (analysis of covariance). FEV1, forced expiratory volume in 1 s.

Figure 4

Change from baseline in trough FEV1at Day 2. Data are presented as least squares means ± standard error: p < 0.0001 versus placebo for all doses of abediterol; **p < 0.01, ***p < 0.001, ****p < 0.0001 (analysis of covariance). FEV1, forced expiratory volume in 1 s.

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