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

Primary Purpose

Asthma

Status

Unknown status

Phase

Not Applicable

Locations

Sweden

Study Type

Interventional

Intervention

Montelukast

Placebo for montelukast

Inhaled leukotriene E4

About this trial

This is an interventional basic science trial for Asthma focused on measuring Leukotriene responsiveness, LTE4, asthma, airway hyperresponsiveness, bronchoprovocation, anti-asthmatic agents, human

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Be aged 18-55 years inclusive
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
Be a non-smoker for the last two years and a total of smoking less than 5 pack-years
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.
Have stable intermittent asthma, only using bronchodilator therapy as needed for the last 4 weeks.
Produce FEV1 (forced expiratory volume in one second) ≥ 70 % of predicted
-

Exclusion Criteria:

Any significant respiratory disease, other than asthma.
Subjects with seasonal asthma may not be included if they are in their season.
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
Upper or lower respiratory tract infection within 4 weeks before inclusion
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
Participating in another study in the four weeks prior to screening
Females who are pregnant, intend to be or who are lactating
Subjects with history of aspirin-sensitive respiratory disease
-

Sites / Locations

Karolinska University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Montelukast

Sugar pill

Arm Description

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.

Placebo for montelukast 5-7 days 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.

Outcomes

Primary Outcome Measures

Bronchoconstriction measured as LTE4 PD20.

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

Airway inflammation measured as sputum eosinophils

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.

Full Information

NCT ID

NCT01841164

First Posted

April 15, 2013

Last Updated

April 23, 2013

Sponsor

Karolinska University Hospital

Collaborators

Karolinska Institutet

1. Study Identification

Unique Protocol Identification Number

NCT01841164

Brief Title

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

Acronym

E-Type

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 Type

Interventional

2. Study Status

Record Verification Date

April 2013

Overall Recruitment Status

Unknown status

Study Start Date

May 2012 (undefined)

Primary Completion Date

June 2014 (Anticipated)

Study Completion Date

December 2014 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Karolinska University Hospital

Collaborators

Karolinska Institutet

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Asthma

Keywords

Leukotriene responsiveness, LTE4, asthma, airway hyperresponsiveness, bronchoprovocation, anti-asthmatic agents, human

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

14 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Montelukast

Arm Type

Experimental

Arm Description

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.

Arm Title

Sugar pill

Arm Type

Placebo Comparator

Arm Description

Placebo for montelukast 5-7 days 2 tablets bid. Efficacy of treatment is evaluated on airway responsiveness to inhaled leukotriene E4.

Intervention Type

Drug

Intervention Name(s)

Montelukast

Other Intervention Name(s)

Singulair

Intervention Type

Drug

Intervention Name(s)

Placebo for montelukast

Intervention Description

Sugar pills manufactured to mimic Singulair

Intervention Type

Other

Intervention Name(s)

Inhaled leukotriene E4

Other Intervention Name(s)

LTE4

Intervention Description

Inhalation challenge with aerosolized GMP-grade LTE4 (Cayman Chemical Company 1180 East Ellsworth Road, Ann Arbor, Michigan 48108,USA)

Primary Outcome Measure Information:

Title

Bronchoconstriction measured as LTE4 PD20.

Description

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.

Time Frame

Up to three years

Secondary Outcome Measure Information:

Title

Airway inflammation measured as sputum eosinophils

Description

Time Frame

Up to three years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Be aged 18-55 years inclusive Have a diagnosed history of asthma as defined by at least one of the following: response to standard asthma treatment episodic wheezing change in lung function over short periods of time Be a non-smoker for the last two years and a total of smoking less than 5 pack-years 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. Have stable intermittent asthma, only using bronchodilator therapy as needed for the last 4 weeks. Produce FEV1 (forced expiratory volume in one second) ≥ 70 % of predicted - Exclusion Criteria: Any significant respiratory disease, other than asthma. Subjects with seasonal asthma may not be included if they are in their season. 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 Upper or lower respiratory tract infection within 4 weeks before inclusion 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 Participating in another study in the four weeks prior to screening Females who are pregnant, intend to be or who are lactating Subjects with history of aspirin-sensitive respiratory disease -

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ann-Sofie Lantz, Registered nurse

Phone

+ 46 8 5858 0000

Ext

6785

Ann-Sofie.Lantz@ki.se

First Name & Middle Initial & Last Name or Official Title & Degree

Nikolaos Lazarinis, MD

Phone

+ 46 8 5858 0000

Ext

6785

Nikolaos.Lazarinis@ki.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Barbro Dahlen, MD PhD

Organizational Affiliation

Karolinska Institutet and Karolinska University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Karolinska University Hospital

City

Stockholm

ZIP/Postal Code

SE -141 86

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ann-Sofie Lantz, RN

Phone

+46 8 58580000

Ext

6785

ann-sofie.lantz@ki.se

First Name & Middle Initial & Last Name & Degree

Barbro Dahlén, MD PhD

First Name & Middle Initial & Last Name & Degree

Nikolaos Lazarinis, MD

First Name & Middle Initial & Last Name & Degree

Johan Larsson, MD

First Name & Middle Initial & Last Name & Degree

Anna James, PhD

First Name & Middle Initial & Last Name & Degree

Craig Wheelock, MA, PhD

First Name & Middle Initial & Last Name & Degree

Sven-Erik Dahlén, MD, PhD

12. IPD Sharing Statement

Citations:

PubMed Identifier

29518425

Citation

Lazarinis N, Bood J, Gomez C, Kolmert J, Lantz AS, Gyllfors P, Davis A, Wheelock CE, Dahlen SE, Dahlen B. Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor. J Allergy Clin Immunol. 2018 Oct;142(4):1080-1089. doi: 10.1016/j.jaci.2018.02.024. Epub 2018 Mar 5.

Results Reference

derived

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

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