Official Title: “A Randomised Double Blind, Placebo Controlled 4-Way Cross Over Study Comparing Montelukast, Inhaled Budesonide and Their Combination on Exercise-Induced Bronchoconstriction”

The purpose of this study is to compare the effects of 2 weeks therapy of montelukast, budesonide, their combination on exercise induced bronchoconstriction (EIB) and airway inflammation in children and young adults, not on regular controller therapy.

Inhaled corticosteroids (ICS) are potent anti-inflammatory agents, which are effective in controlling and improving all aspects of asthma including the attenuation of EIB. However, the effect of ICS monotherapy on EIB is comparable if not inferior to the effect of CysLTs modifiers alone. This may be due to the lack of effect of ICS on the CysLT pathway. As a consequence, we hypothesize that the combination of ICS and CysLT modifiers will offer a greater protection against EIB than either therapy alone.The different classes of drugs may act on complementary pathways believed to be important in the pathophysiology of EIB.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: September 2008

The study will be a 2 centre randomised, double blind, placebo controlled 4-way cross over study comparing montelukast, budesonide and their combination on exercise-induced bronchoconstriction (EIB). Subjects with stable mild to moderate asthma, between the ages of 8-35 years, not on controller asthma therapy will be screened. A maxFEV1% ≥15% following a standardized dry air exercise challenge at screening (SC) and following a 1 week run-in (V-1) is required to qualify. Once qualified, subjects will return the following day (V0) for a skin prick test and a methacholine inhalation test before being randomised to 1 of 4 treatment sequences. Each treatment will be given for a total of 14 days with a 4 weeks washout. During each period, subjects will attend the laboratory on 2 occasions, at the beginning and end of each period. Baseline spirometry; eNO; EBC will be performed, followed by an exercise challenge with serial FEV1 and eNO measurements up to 30 minutes post exercise and post-exercise EBC and sputum induction at each evaluation visit. There will be a total of 10 visits and the duration of study will be approximately 148 days (21 weeks). All visits will be scheduled within 2 hours of the post-run visit (V1) and at least 8 hours after the last dose of trial medications.

Investigational Product, Dose and Administration:

Montelukast 5mg (<15 years) or 10mg (and matching placebo) will be taken 1 tablet in the evening together with inhaled budesonide turbuhalers 200ug (and matching placebo) taken 1 puff in the morning and 1 puff in the evening.

Efficacy on EIB:

The changes between pre and post treatment exercise-induced maxFEV1% and area under the curve (AUC0-30) will be compared between the 4 periods. MaxFEV1% will be calculated as pre-exercise FEV1 minus post exercise lowest FEV1 divided by pre-exercise FEV1 multiplied by 100; AUC will be calculated using the trapezoidal rule. The protection provided by the active treatments will be defined as the pre-treatment maxFEV1% minus post-treatment maxFEV1% divided by pre-treatment maxFEV1% x 100. The proportions of subjects attaining ≥50% protection will be compared between the 4 arms.

Efficacy on eNO and inflammatory parameters measured in sputum and EBC Changes in % and absolute counts of sputum differential cells, eNO and inflammatory mediators (in EBC/ sputum) at baseline and in response to exercise will be compared between the 4 arms.

Intervention(s) in this Clinical Trial

• Drug: budesonide
  • montelukast 5 mg ( < 15 years) or 10 mg (& matching placebo)will be taken 1 tab in the evening together with inhaled budesonide turbuhaler 200ug (& matching placebo) taken 1 puff morning & 1 puff evening.
• Drug: montelukast
  • montelukast 5 mg ( < 15 years) or 10 mg (& matching placebo)will be taken 1 tab in the evening together with inhaled budesonide turbuhaler 200ug (& matching placebo) taken 1 puff morning & 1 puff evening.
• Drug: montelukast & budesonide
  • montelukast 5mg ( < 15 years) or 10 mg (& matching placebo)will be taken 1 tab in the evening together with inhaled budesonide turbuhaler 200 ug (& matching placebo) taken 1 puff morning & 1 puff evening.
• Other: placebo
  • placebo

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • montelukast
• Active Comparator: 2
  • budesonide
• Placebo Comparator: 3
  • placebo
• Active Comparator: 4
  • montelukast budesonide combination

Primary Measures

• The magnitude of protection and the number of subjects with ≥50% protection (considered to be clinically relevant) following treatment
  • Time Frame: Before and after 2 weeks of treatment in each 4 arm
    Safety Issue?: No

Secondary Measures

• Change in sputum cell counts and fluid phase inflammatory mediators
  • Time Frame: Before and after 2 weeks of treatment in each 4 arm
    Safety Issue?: No
• Change in baseline exhaled nitric oxide (eNO) and response to exercise challenge
  • Time Frame: Before and after 2 weeks of treatment in each 4 arm
    Safety Issue?: No
• Change in EBC (exhaled breath condensate) inflammatory mediators from baseline
  • Time Frame: Before and after 2 weeks of treatment in each 4 arm
    Safety Issue?: No
• The change in exercise induced maximal percent fall in FEV1 (maxFEV1%) and area under the curve (AUC0-30) relative to pre-exercise FEV1 up to 30 minutes following exercise challenge
  • Time Frame: Before and after 2 weeks of treatment in each 4 arm
    Safety Issue?: No

Inclusion Criteria:

• Males or females ages 8-35 years with stable mild-to-moderate asthma (ATS criteria) not on regular controller therapy
• Prebronchodilator FEV1 predicted ≥ 70%
• No other medical co-morbidity
• Demonstrate maxFEV1% ≥15% on exercise challenge at screening and 1 week post run-in.

Exclusion Criteria:

• Asthma exacerbations or respiratory infection within 4 weeks of screening
• Recent use of inhaled or systemic steroids
• Immunosuppressives
• Antihistamines, NSAIDs and investigational drugs within 30 days
• Unable to reliably perform spirometry and exercise challenge
• Current or ex-smokers ≥ 10 pack-years and less than 1 month abstinence
• Contra-indications to inhaled steroids or montelukast use.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 8 Years

Maximum Age for this Clinical Trial: 35 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Hamilton Health Sciences

Overall Clinical Trial Officials and Contacts

Paul O'Byrne, MD Principal Investigator Hamilton Health Sciences  

Overall Contact: Mylinh Duong, MD 905-525-9140 duongmy@univmail.cis.mcmaster.ca

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00462592

Study ID Number: monbud8035

ClinicalTrials.gov Identifier: NCT00462592

Health Authority: Canada: Health Canada