Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to see whether a new investigational drug (Imatinib) may help
      improve asthma in people whose symptoms are not well controlled with high dose inhaled
      corticosteroid treatment.
    

Detailed description: 
      Severe asthmatics remain poorly controlled despite high doses of standard asthma therapy or
      even daily doses of systemic corticosteroids or their equivalent. They account for a large
      proportion of the morbidity and mortality associated with asthma. Features that seem to
      characterize many patients with this disorder include persistent inflammation, symptoms, and
      airway hyperresponsiveness in the face of corticosteroid therapy. Mast cells are powerful,
      long-lived tissue dwelling effector cells that are resistant to corticosteroid effects and
      have been implicated in the pathobiology of asthma. Mast cells in the airway smooth muscle
      have been found to be the major distinguishing difference between asthmatic and non-asthmatic
      eosinophil airway disease; and putative circulating mast cell progenitors are increased 5
      fold in asthma. Stem cell factor (SCF) is critical to mast cell homeostasis and upregulation
      and has pleiotropic effects on mast cells and eosinophils . SCF levels are elevated in
      relation to asthma severity and SCF antibodies block hyperresponsiveness and inflammation and
      remodeling in murine asthma models. Imatinib, a specific tyrosine kinase inhibitor, inhibits
      cKit (Kit), the receptor for SCF on mast cells. Imatinib at doses equivalent to, or below,
      doses safely used in humans, also mimics or exceeds anti-SCF effects in the murine asthma
      model. Therefore we would like to know Does imatinib, an inhibitor of Kit, ameliorate severe
      asthma, in association with effects on lung mast cell phenotype and/or function?

      Specific Aims of the study are:

      Specific Aim 1: To investigate whether, in patients with persistent airway responsiveness and
      poor asthma control despite intensive asthma therapy, 24 weeks of imatinib therapy results in
      a reduction in airway responsiveness and in secondary indicators of asthma control, airway
      inflammation, and structural changes in the airways.

      Patients will be treated with imatinib in a randomized, double-blind, placebo controlled
      trial. Assessments will include methacholine and AMP reactivity, airway function, symptoms,
      airway wall thickness by CT scan, analysis of induced sputum, non-invasive markers of airway
      inflammation, and bronchoscopy including endobronchial biopsy and bronchoalveolar lavage -
      all before and at the end of therapy.

      Specific Aim 2: To investigate whether, in patients with persistent airway responsiveness and
      poor asthma control despite intensive asthma therapy, 24 weeks of imatinib therapy results in
      changes in airway mast cell population and/or phenotype.
    

Intervention name(s): Imatinib mesylate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Imatinib will be initiated at an oral dose of 200 mg (two 100 mg film-coated tables) per day during the first two weeks of treatment. If the treatment is well tolerated, an up-titration to 400 mg daily (four 100 mg film-coated tables) will occur.; Placebo
Other intervention name(s): Gleevec, Zoleta, Glivec, Ziatir
Intervention MeSH terms: Imatinib Mesylate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: cKIT inhibition in Asthma; Efficacy of Imatinib in severe resistent asthma.