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

Not Applicable

• Conditions: Asthma
• Interventions: Drug: Placebo for montelukast; Drug: Montelukast; Other: Inhaled leukotriene E4

• Registration Number: NCT01841164
• Lead Sponsor: Karolinska University Hospital

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study Start: 2012-05
• Status Verified: 2013-04
• Study First Submitted: 2013-04-15
• Study First Submitted QC: 2013-04-23
• Last Update Submitted: 2013-04-23
• Study First Posted: 2013-04-26
• Last Update Posted: 2013-04-26
• Primary Completion: 2014-06
• Study Completion: 2014-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

1. Be aged 18-55 years inclusive

2. Have a diagnosed history of asthma as defined by at least one of the following:

   1. response to standard asthma treatment
   2. episodic wheezing
   3. change in lung function over short periods of time

3. Be a non-smoker for the last two years and a total of smoking less than 5 pack-years

4. Display a positive methacholine challenge test as evidenced by a PD20 (provocative dose causing 20% fall in forced expiratory volume in one second) ≤ 3621 µg cumulated dose within 8 weeks prior to screening or at the screening visit.

5. Have stable intermittent asthma, only using bronchodilator therapy as needed for the last 4 weeks.

6. Produce FEV1 (forced expiratory volume in one second) ≥ 70 % of predicted

Exclusion Criteria

1. Any significant respiratory disease, other than asthma.

2. Subjects with seasonal asthma may not be included if they are in their season.

3. Use of:

   • oral or inhaled glucocorticosteroid treatment for the last 4 weeks prior to inclusion or during the study
   • inhaled long-acting or oral beta2-agonists, anticholinergic bronchodilators, antihistamines, theophyllines, chromones and antileukotrienes within 2 weeks of screening
   • regular NSAIDs
   • drugs that inhibit the enzyme CYP3A (e.g. ritonavir, azol, antifungals, macrolides)
   • beta-blocking agents

4. Upper or lower respiratory tract infection within 4 weeks before inclusion

5. Evidence (from medical history or physical examination) of any disease that in the investigators mind would affect the results of the study, in particular liver disease and/or signs of liver function impairment

6. Participating in another study in the four weeks prior to screening

7. Females who are pregnant, intend to be or who are lactating

8. Subjects with history of aspirin-sensitive respiratory disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Montelukast	Inhaled leukotriene E4	5 to 7 days of treatment with montelukast 10 mg 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.
Sugar pill	Inhaled leukotriene E4	Placebo for montelukast 5-7 days 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.
Sugar pill	Placebo for montelukast	Placebo for montelukast 5-7 days 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.
Montelukast	Montelukast	5 to 7 days of treatment with montelukast 10 mg 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.

Primary Outcome Measures

Name	Time	Method
Bronchoconstriction measured as LTE4 PD20.	Up to three years	To 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.

Secondary Outcome Measures

Name	Time	Method
Airway inflammation measured as sputum eosinophils	Up to three years	To establish the effect of oral treatment with the highly selective CysLT1-receptor antagonist montelukast on airway inflammation, assessed as sputum cells, induced by inhaled LTE4, in subjects with intermittent asthma.

Trial Locations

Locations (1)

Karolinska University Hospital; 🇸🇪 Stockholm, Sweden