A Mechanistic Study to Evaluate the Efficacy of Montelukast on Airway Function in Asthma (E-Type)

April 23, 2013 updated by: Barbro Dahlen, Karolinska University Hospital

A Study of the Effects of the Selective CysLT1 Antagonist Montelukast on Bronchoconstriction and Airway Inflammation Induced by Inhalation of Leukotriene E4 in Subjects With Asthma

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

14

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
      • Stockholm, Sweden, SE -141 86
        • Recruiting
        • Karolinska University Hospital
        • Contact:
        • Principal Investigator:
          • Barbro Dahlén, MD PhD
        • Sub-Investigator:
          • Nikolaos Lazarinis, MD
        • Sub-Investigator:
          • Johan Larsson, MD
        • Sub-Investigator:
          • Anna James, PhD
        • Sub-Investigator:
          • Craig Wheelock, MA, PhD
        • Sub-Investigator:
          • Sven-Erik Dahlén, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 55 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Montelukast
Other Names:
  • Singulair
Other: Inhaled leukotriene E4
Inhalation challenge with aerosolized GMP-grade LTE4 (Cayman Chemical Company 1180 East Ellsworth Road, Ann Arbor, Michigan 48108,USA)
Other Names:
  • LTE4
Placebo Comparator: Sugar pill
Placebo for montelukast 5-7 days 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.
Other: Inhaled leukotriene E4
Inhalation challenge with aerosolized GMP-grade LTE4 (Cayman Chemical Company 1180 East Ellsworth Road, Ann Arbor, Michigan 48108,USA)
Other Names:
  • LTE4
Drug: Placebo for montelukast
Sugar pills manufactured to mimic Singulair

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bronchoconstriction measured as LTE4 PD20.
Time Frame: 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.
Up to three years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Airway inflammation measured as sputum eosinophils
Time Frame: 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.
Up to three years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Karolinska University Hospital

Collaborators

Karolinska Institutet

Investigators

  • Principal Investigator: Barbro Dahlen, MD PhD, Karolinska Institutet and Karolinska University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2012

Primary Completion (Anticipated)

June 1, 2014

Study Completion (Anticipated)

December 1, 2014

Study Registration Dates

First Submitted

April 15, 2013

First Submitted That Met QC Criteria

April 23, 2013

First Posted (Estimate)

April 26, 2013

Study Record Updates

Last Update Posted (Estimate)

April 26, 2013

Last Update Submitted That Met QC Criteria

April 23, 2013

Last Verified

April 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • E-Type 4 KI_Cfa

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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