Effect of Montelukast on the Airway Remodeling
Condition: Asthma
MeSH terms: Asthma; Airway Remodeling
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): singular; placebo
Intervention type(s): Drug; Drug
Intervention description(s): The participants randomized into this arm will receive singular 10mg q.n. plus combine therapy with inhaled ICS+LABA; The participants allocated into this arm will receive placebo 10mg,q.n plus combine therapy with inhaled ICS+LABA
Other intervention name(s): montelukast
Intervention MeSH terms: Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: antileukotriene; small airway; airway remodeling; HRCT