Effect of Montelukast on the Airway Remodeling

January 3, 2012 updated by: Jinming Gao, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Effect of Montelukast on the Airway Remodeling in Asthma Patients: Physiological-radiological Correlation

The distal lung contributes to asthmatic airway remodeling which is observed from early onset of the disease. Cysteinyl leukotrienes (CysLT) play important role in the pathogenesis of airway remodeling and antileukotrienes work to exert a certain degree of anti-inflammatory effect. The cysteinyl leukotriene antagonist Montelukast has been in vivo shown to significantly inhibit ovalbumin induced airway smooth muscle hyperplasia and subepithelial fibrosis in sensitized mice. This study aims to evaluate if Montelukast could reverse airway remodeling in asthma patients by a non-invasive approach-HRCT.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Accumulated data have suggested that the distal lung, which includes airways of < 2mm in diameter and lung parenchyma, contribute to asthma pathogenesis and symptoms. In addition to persisting inflammation, distal lung undergoes remodeling, as demonstrated by the reduced elastic fiber content and abnormal alveolar attachments, with the latter thought to result in a loss of elastic recoil and a reduction in FEV1.0. Furthermore, recent studies have shown that airway remodeling is observed from early onset of the disease and may, therefore, be characteristic of asthma. Amounting evidence has revealed that airway remodeling of asthmatic airways accounts for a large component of airway hyperresponsiveness (AHR) and excessive airway narrowing.

Since remodeling processes occur in parallel to, or may even be obligatory for, the establishment of persistent inflammation, the pathogenesis of airway remodeling and the implications of therapeutic interventions that are designed to diminish airway remodeling remain important areas of both research and clinic. Inhale corticosteroid (ICS) is mainstay for the treatment of asthma, however, ICS provides very little benefit for airway remodeling.

Cysteinyl leukotrienes (CysLT) play important role in the pathogenesis of airway remodeling and antileukotrienes work to exert a certain degree of anti-inflammatory effect. The cysteinyl leukotriene antagonist Montelukast, for example, has been in vivo shown to significantly inhibit ovalbumin induced airway smooth muscle hyperplasia and subepithelial fibrosis in sensitized mice. Montelukast, a systemically delivered leukotriene receptor antagonist, has been strongly recommended to treat asthma by several guidelines. Clinically, the systemically acting oral agent montelukast has been shown to improve proximal and distal lung physiology. In particular, improvements in distal lung function correlate with improvements in asthma symptoms. The in vivo experiments performed in rodent animal challenged by OVA have shown that Montelukast can reverse airway remodeling, as well as inhibit inflammation.

To determine the occurrence of airway remodeling in human being, bronchial biopsy samples obtained with a bronchoscope are subjected to histological examination. However, bronchial biopsy is invasive and causes considerable pain, while assessment of the peripheral small airways and of changes in the deep submucosal tissue and airway smooth muscle in large airways is technically difficult. This technique does not allow the longitudinal analysis of airway wall dimensions.

Noninvasive evaluation of airways by means of imaging with high-resolution computed tomography (HRCT) has therefore been tried as an alternative procedure, and was found to have the potential to evaluate airways in patients with obstructive pulmonary disease. The measurement of airway wall thickness by HRCT in patients with asthma has been demonstrated to correlate with the severity of asthma. Computed tomographic imaging of the airways by HRCT has been widely applied to investigate the alterations in the structure of the airways termed airway remodeling in patients with airway obstructive diseases (see references 1-4).

So far to our knowledge, there is no study aiming to evaluate if Montelukast could reverse airway remodeling in asthma patients by HRCT.

Our encouraging preliminary data performed in 4 patients with moderate to severe asthma according to GINA definition who received oral Montelukast for 3 months demonstrate with or without combination of ICS+LABA that there were significant improvements in airway wall thickness and air trapping evaluated by measurement of HRCT and lung function in patients with oral Montelukast as compared with those without oral Montelukast. We adopted WA% and WA/BSA to reflect the degree of airway thickness as published methods. We found that the patients who received oral montelukast for 3 months experienced improvements in airway remodeling. WA/BSA and WA% significantly decreased compared to the baseline.

The purpose of the proposal presented is to further examine, in a relatively large number of patients, that Montelukast can improve the structural changes in the large airways and air trapping by means of HRCT, and their relationship with pulmonary function in patients in moderate to severe asthma.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 4

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

  • China
      • Beijing, China, 100730
        • Peking Union Medical College Hospital

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

16 years to 65 years (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • forced expiratory volume in one second (FEV1) is at 60-80% predicted or less than 60% predicted
  • clinical diagnosis of moderate-to-severe asthma.

Exclusion Criteria:

  • intravenous, oral or intramuscular steroids used within 1 months
  • Anti-leukotrienes, cromolyn sodium or nedocromil used within 2 months
  • Theophylline or beta-adrenergic blockers used within 1 month
  • Tobacco Used within the past year or cumulative smoking history > 5 pack-yrs
  • Respiratory infection or an influenza vaccination Within 3 weeks
  • Pregnant or lactating females
  • Patient has a history of an anaphylactic allergic reaction related to administration of either a marketed or investigational drug

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: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Placebo pill
The patients allocated into this placebo comparator arm will receive inhale corticosteroid plus long-acting bronchodilator plus placebo for 6 months.
Drug: placebo
The participants allocated into this arm will receive placebo 10mg,q.n plus combine therapy with inhaled ICS+LABA
EXPERIMENTAL: Singular pill
The patients in this placebo comparator arm will receive inhale corticosteroid plus long-acting bronchodilator and montelukast for 6 months
Drug: singular
The participants randomized into this arm will receive singular 10mg q.n. plus combine therapy with inhaled ICS+LABA
Other Names:
  • montelukast

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate distal airway function using high-resolution CT and lung function test
Time Frame: 6 months
To demonstrate that the correlation between non-invisive chest HRCT and lung function test in patients moderate-to-severe asthma
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montelukast can bring additional benefit for lung function improvement in moderate to severe patients with asthma
Time Frame: 6 months
To test whether montelukast can improve the distal airway function
6 months

Collaborators and Investigators

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

Sponsor

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Investigators

  • Principal Investigator: Jinming Gao, M.D., Ph.D., Peking Union Medical College 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

Helpful Links

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

January 1, 2010

Primary Completion (ACTUAL)

January 1, 2012

Study Completion (ACTUAL)

January 1, 2012

Study Registration Dates

First Submitted

June 11, 2008

First Submitted That Met QC Criteria

June 16, 2008

First Posted (ESTIMATE)

June 17, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

January 5, 2012

Last Update Submitted That Met QC Criteria

January 3, 2012

Last Verified

January 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JGao001
  • Merck-IISP001 (OTHER_GRANT: MSD pharmaceutical)

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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