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

Brigham and Women's Hospital176 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

176

Conditions

Asthma

Interventions

Imatinib mesylateDRUG

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.

PlaceboDRUG

Placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients 18-65 years of age, diagnosed with asthma for at least 1 year; 2. 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: 1. Current smoking or smoking history of greater than 10 pack-years 2. Any other significant respiratory or cardiac disease, or the presence of clinically important comorbidities, including uncontrolled diabetes, uncontrolled coronary artery disease 3. If subject cannot undergo bronchoscopy procedure due to safety reasons 4. Previous treatment with Imatinib 5. A history of acute heart failure or chronic left sided heart failure 6. Uncontrolled systemic arterial hypertension 7. History of major bleeding or intracranial hemorrhage 8. History of immunodeficiency diseases, including HIV 9. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer 10. 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. 11. Diagnosis of Hepatitis B or C. 12. History of alcohol abuse within 6 months of screening. 13. History of illicit drug abuse within 6 months of screening. 14. Regular use of anticoagulants (eg: Warfarin Sodium, Coumadin), amiodarone, carbamazepine, Cyclosporine, Rifampicin, or reverse transcriptase inhibitors

Locations (7)

University of Alabama

Birmingham, Alabama, United States

Brigham and Womens Hospital

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Columbia University

New York, New York, United States

Outcomes

Primary Outcomes

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).

Time frame: Over 6 months from beginning of treatment

Secondary Outcomes

Serum Total Tryptase

Change in serum total tryptase after 24 weeks of imatinib vs placebo treatment

Time frame: 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

Time frame: 6 months after start of treatment

Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) %

Time frame: 6 months after start of treatment

Number of Asthma Exacerbations

Number of asthma exacerbations experienced from randomization to study completion.

Time frame: Up to 24 weeks

FEV1 in Liters

Change in FEV1 in treatment group compared to placebo group

Data from ClinicalTrials.gov

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