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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01841164
Recruitment Status : Unknown
Verified April 2013 by Barbro Dahlen, Karolinska University Hospital.
Recruitment status was:  Recruiting
First Posted : April 26, 2013
Last Update Posted : April 26, 2013
Sponsor:
Collaborator:
Karolinska Institutet
Information provided by (Responsible Party):
Barbro Dahlen, 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


Condition or disease Intervention/treatment Phase
Asthma Drug: Montelukast Drug: Placebo for montelukast Other: Inhaled leukotriene E4 Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: 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
Study Start Date : May 2012
Estimated Primary Completion Date : June 2014
Estimated Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
Drug Information available for: Montelukast

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 Name: 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 Name: 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.
Drug: Placebo for montelukast
Sugar pills manufactured to mimic 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 Name: LTE4




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    -


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01841164


Contacts
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Contact: Ann-Sofie Lantz, Registered nurse + 46 8 5858 0000 ext 6785 Ann-Sofie.Lantz@ki.se
Contact: Nikolaos Lazarinis, MD + 46 8 5858 0000 ext 6785 Nikolaos.Lazarinis@ki.se

Locations
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Sweden
Karolinska University Hospital Recruiting
Stockholm, Sweden, SE -141 86
Contact: Ann-Sofie Lantz, RN    +46 8 58580000 ext 6785    ann-sofie.lantz@ki.se   
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         
Sponsors and Collaborators
Karolinska University Hospital
Karolinska Institutet
Investigators
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Principal Investigator: Barbro Dahlen, MD PhD Karolinska Institutet and Karolinska University Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Barbro Dahlen, Senior Consultant, MD PhD, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT01841164    
Other Study ID Numbers: E-Type 4 KI_Cfa
First Posted: April 26, 2013    Key Record Dates
Last Update Posted: April 26, 2013
Last Verified: April 2013
Keywords provided by Barbro Dahlen, Karolinska University Hospital:
Leukotriene responsiveness
LTE4
asthma
airway hyperresponsiveness
bronchoprovocation
anti-asthmatic agents
human
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Montelukast
Anti-Asthmatic Agents
Respiratory System Agents
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP1A2 Inducers
Cytochrome P-450 Enzyme Inducers
Molecular Mechanisms of Pharmacological Action