A Mechanistic Study to Evaluate the Efficacy of Montelukast on Airway Function in Asthma

Overview

The trial is an investigator-driven research study in subjects with intermittent asthma, the aim of which is to explore the likelihood of a functionally important separate leukotriene E4 (LTE4) receptor in airways and/or inflammatory cells in human subjects with asthma. Mostly on the basis of experiments in mice models, the prevailing view suggests that the present class of anti-leukotriene drugs are insufficient because they do not block the pro-inflammatory and bronchoconstrictive effects of LTE4. It is established by us and other groups that LTE4 is the most stable and long-lived leukotriene. The study will establish the effect of oral treatment with the highly selective CysLT1-receptor antagonist, montelukast, on bronchial responsiveness to inhaled LTE4 in subjects with intermittent asthma

Rationale: It has been proposed that there is a specific LTE4-receptor which causes infiltration of inflammatory cells and bronchoconstriction. This receptor is not blocked by the current class of clinically used antileukotriene drugs. The proposal receives circumstantial support from animal models, but has not been tested in a controlled study in subjects with asthma. Study design: The study will have a placebo-controlled, double-blind, randomised, cross-over design. A screening period will precede the randomized phase. This will include routine haematology, blood chemistry and urinalyses, baseline measurements of exhaled nitric oxide, airway responsiveness to inhaled methacholine and, on a separate day, airway responsiveness to inhaled LTE4. Provided the subjects fulfill inclusion but not exclusion criteria, subjects will be randomized to receive medication with montelukast or matching placebo for 5 to 7 days. The intervention will be evaluated in the inhalation challenge setting using a rising dose cumulative protocol for inhaled LTE4 to induce a standardised bronchoconstriction (25% drop in lung function). The LTE4 challenge test is performed on the last treatment day, with the last dose of study medication taken in the research laboratory. Sampling of urine, blood and induced sputum will be done for measurements of lipid mediators and cellular responses.