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Effect of Montelukast on the Airway Remodeling

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: NCT00699062
Recruitment Status : Completed
First Posted : June 17, 2008
Last Update Posted : January 5, 2012
Sponsor:
Information provided by (Responsible Party):
Jinming Gao, Chinese Academy of Medical Sciences

Tracking Information
First Submitted Date  ICMJE June 11, 2008
First Posted Date  ICMJE June 17, 2008
Last Update Posted Date January 5, 2012
Study Start Date  ICMJE January 2010
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 3, 2012)
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
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2008)
Montelukast can improve lung function including proximal and distal airways and reverse airway remodeling in moderate to severe patients with asthma. [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2012)
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
Original Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2008)
Montelukast can bring additional benefit for lung function improvement in moderate to severe patients with asthma [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Montelukast on the Airway Remodeling
Official Title  ICMJE Effect of Montelukast on the Airway Remodeling in Asthma Patients: Physiological-radiological Correlation
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: singular
    The participants randomized into this arm will receive singular 10mg q.n. plus combine therapy with inhaled ICS+LABA
    Other Name: montelukast
  • Drug: placebo
    The participants allocated into this arm will receive placebo 10mg,q.n plus combine therapy with inhaled ICS+LABA
Study Arms  ICMJE
  • 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.
    Intervention: Drug: placebo
  • Experimental: Singular pill
    The patients in this placebo comparator arm will receive inhale corticosteroid plus long-acting bronchodilator and montelukast for 6 months
    Intervention: Drug: singular
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2008)
40
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 2012
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00699062
Other Study ID Numbers  ICMJE JGao001
Merck-IISP001 ( Other Grant/Funding Number: MSD pharmaceutical )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jinming Gao, Chinese Academy of Medical Sciences
Study Sponsor  ICMJE Chinese Academy of Medical Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jinming Gao, M.D., Ph.D. Peking Union Medical College Hospital
PRS Account Chinese Academy of Medical Sciences
Verification Date January 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP