A Phase I Randomized, Placebo-Controlled, Dose-Exploration Study of Single-Dose Inhaled Montelukast in Patients with Chronic Asthma

Background. The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast. Methods. Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15-65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 mu g, and doses of 50, 100, and 500 mu g could be used if needed based on a prespecified dose-response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV1) over the first 4 hours after administration, calculated as a time-weighted average (Delta FEV1 [0-4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast. Results. Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 mu g (0.13 L; p <= .001), 250 mu g (0.10 L; p < .01), and 1000 mu g (0.12 L; p <= .001) had significantly greater Delta FEV1 (0-4 hours). At 24 hours postdose, inhaled montelukast 100 mu g (0.10 L) and 1000 mu g (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 mu g provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. -0.05 L), whereas montelukast 100 mu g provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for Delta FEV1 (0-90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported. Conclusions. Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.