Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A 28 Week, Treatment Randomized, Double -Blind, Placebo-controlled Study of the Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)

Conditions
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Asthma

Intervention / Treatment
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* Drug: Imatinib mesylate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18-65 years of age, diagnosed with asthma for at least 1 year; Refractory asthma, defined as reporting that their asthma has not been completely controlled in the past 3 months despite continuous treatment with high-dose inhaled corticosteroids (ICS) and an additional controller medication, with or without continuous oral corticosteroids (OCS) Exclusion Criteria: Current smoking or smoking history of greater than 10 pack-years Any other significant respiratory or cardiac disease, or the presence of clinically important comorbidities, including uncontrolled diabetes, uncontrolled coronary artery disease If subject cannot undergo bronchoscopy procedure due to safety reasons Previous treatment with Imatinib A history of acute heart failure or chronic left sided heart failure Uncontrolled systemic arterial hypertension History of major bleeding or intracranial hemorrhage History of immunodeficiency diseases, including HIV Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. Diagnosis of Hepatitis B or C. History of alcohol abuse within 6 months of screening. History of illicit drug abuse within 6 months of screening. Regular use of anticoagulants (eg: Warfarin Sodium, Coumadin), amiodarone, carbamazepine, Cyclosporine, Rifampicin, or reverse transcriptase inhibitors

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Imatinib mesylate<br>Group on active imatinib treatment | Drug: Imatinib mesylate<br>* 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.<br>* Other names: Gleevec, Zoleta, Glivec, Ziatir;|
| Placebo Comparator: Placebo<br>Group on Placebo treatment | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Methacholine Responsiveness as Assessed by the Provocation Concentration Causing a 20% Fall in Forced Expiratory Volume in One Second (FEV1) (PC20) at Month 3 and 6 Versus Baseline | Our primary outcome was change in airway hyperresponsiveness, as assessed by PC20, from baseline to 3 and/or 6 months of therapy in imatinib treated participants as compared with controls. Change in PC20 was assessed using log2-transformed ratios of PC20 at month 3 and /or month 6 vs PC20 at baseline. Our null hypothesis was that the mean of this ratio will be 0 after log2-transformed. We used a linear mixed-effects model for a repeated-measures analysis to compare the primary outcome between the two groups. PC20 is determined by the provocation concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1). | Over 6 months from beginning of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Total Tryptase | Change in serum total tryptase after 24 weeks of imatinib vs placebo treatment | 6 months after start of treatment | 
| Bronchoalveolar Lavage (BAL) Fluid Tryptase Level | Change in BAL fluid tryptase levels after 24 weeks of imatinib vs. placebo | 6 months after start of treatment | 
| Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) % |  | 6 months after start of treatment | 
| Number of Asthma Exacerbations | Number of asthma exacerbations experienced from randomization to study completion. | Up to 24 weeks | 
| FEV1 in Liters | Change in FEV1 in treatment group compared to placebo group | 6 months after start of treatment | 
| FEV1% | Change in FEV1% of predicted | 6 months after start of treatment | 
| Morning Peak Flow Measurement | Change in patient-reported morning peak flow measurement (L/s) | 6 months after start of treatment | 
| Evening Peak Flow | Change in patient-reported evening peak flow measurement (L/s) | 6 months after start of treatment | 
| Fractional Exhaled Nitric Oxide (FeNO) | Change in Fractional Exhaled Nitric Oxide Measurement (ppb) | 6 months after start of treatment | 
| Asthma Control Questionnaire (ACQ) | Change in patient-reported ACQ score The six-item Asthma Control Questionnaire (ACQ-6) is a scale from 0 to 6 with a lower value denoting an improvement in asthma control. The minimal important difference is 0.5. | 6 months after start of treatment | 
| Asthma Quality of Life Questionnaire (AQLQ) | Change in patient-reported Asthma Quality of Life Questionnaire (AQLQ) score The asthma quality of life questionnaire (AQLQ) is a 32-item scale with a range from 1-7 with a higher value denoting improvement. The minimal important difference is 0.5. | 6 months after start of treatment | 
| Asthma Symptom Utility Index (ASUI) | Change in patient reported ASUI score The asthma symptom utility index (ASUI) is a 10-item weighted scale with a range from 0.2 to 1 with a higher value indicating improvement. The minimal important difference is 0.09. | 6 months after start of treatment | 
| BAL Neutrophil % | Change in BAL neutrophil percentage from baseline | 6 months after start of treatment | 
| BAL Eosinophil % | Change in BAL eosinophil percentage | 6 months after start of treatment | 
| Bronchoalveolar Lavage (BAL) PGD2 | Change in bronchoalveolar lavage (BAL) PGD2 levels from baseline at 6 months | 6 months after start of treatment | 
| Endobronchial Biopsy Total Tryptase-positive Mast Cells | Change in endobronchial biopsy total tryptase-positive mast cells from baseline at 6 months | 6 months after start of treatment | 
| Endobronchial Biopsy Smooth Muscle Tryptase-positive Mast Cells | Change in the biopsy smooth muscle tryptase-positive mast cells from baseline at 6 months | 6 months after start of treatment | 
| Blood Eosinophils | Change in blood eosinophil count | 6 months after start of treatment | 
| Airway Wall Thickness | Change in airway wall thickness as assessed by computerized tomography (CT) | 6 months after start of treatment | 
| Airway Wall Area | Change in airway wall area as assessed by computerized tomography (CT) | 6 months after start of treatment | 
| Bronchoalveolar Lavage Histamine | Change in bronchoalveolar lavage histamine levels from baseline | 6 months after start of treatment | 
| Urinary Prostaglandin D2 | Change in urinary Prostaglandin D2 levels from baseline | 6 months after start of treatment | 
| Bronchoalveolar Lavage Cysteinyl Leukotrienes | Change in bronchoalveolar lavage cysteinyl leukotrienes levels from baseline | 6 months after start of treatment | 
| Urinary Leukotriene E4 | Change in urinary leukotriene E4 levels from baseline | 6 months after start of treatment | 
| Change in Sputum Supernatant Differential, Supernatant Tryptase and IL-13 | Change in sputum eosinophil and neutrophil percentage. Change in sputum supernatant tryptase as measured by ELISA. Change in sputum IL-13 level as measured by ELISA. | baseline to 24 weeks | 
| Change in Inflammatory Mediators in Exhaled Breath Condensate | Assessment of change in eicosanoids in the exhaled breath condensate | baseline to week 24 | 
| Change in Number of Self-Reported Asthma Symptom Free Days |  | baseline to week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cKIT inhibition in Asthma, Efficacy of Imatinib in severe resistent asthma.