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

Abstract

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 μg, and doses of 50, 100, and 500 μg 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 (ΔFEV₁ [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 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p < .01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV₁ (0–4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. –0.05 L), whereas montelukast 100 μg 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 ΔFEV₁ (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.

Keywords:

• asthma
• FEV₁
• clinical trial
• Phase I
• montelukast
• placebo

Acknowledgments

All authors are responsible for the work described in this article. All were involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, interpretation of data, and drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published.

The authors thank Jolanta Strus, M.D., for her contributions to the conduct of the study, Qian Wang for her contributions to the statistical programming, and Jennifer Pawlowski for her help with the preparation of the manuscript.

Protocol 388 Investigators: Thomas Casale, MD, Omaha, NE; Phillip E. Korenblat, MD, St. Louis MO; S. David Miller, MD, North Dartmouth, MA; Mark H. Moss, MD, Madison, WI; Andrew Pedinoff, MD, Skillman, NJ; Kenneth Rundell, MD, Scranton, PA.****

Declaration Of Interest

This study was supported by Merck & Co., Inc. Drs. Philip, Tymofyeyev, and Smugar and Ms. Vandormael are employees of Merck who may potentially own stock and/or hold stock options in the company. Dr. Reiss was an employee of Merck at the time of the conduct of the study and is presently employed by Covance, Inc., Princeton, NJ, USA. Dr. Pedinoff reports no conflicts of interest. Dr. Korenblat has been a consultant for MediciNova, Inc., has been on the speaker's bureau for and received honorarium from Genentech and Novartis, and holds stock in Alcon, Biotech Holdings, Johnson & Johnson, GlaxoSmithKline, and King Pharmaceuticals. He has received grant or research support from Amgen, Antigen Laboratories, Astellas, AstraZeneca, Capnia, Centocor, Forest, Genentech, GlaxoSmithKline, Icagen, MAP Pharmaceuticals, Meda Pharmaceuticals, MedImmune, Novartis, Pfizer, Renovo, Sanofi Pasteur, Schering-Plough, Sepracor, Sallergenes, and Teva.