Clinical trial NCT01097694: Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: cKIT inhibition in Asthma
Efficacy of Imatinib in severe resistent asthma.
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Baim Institute for Clinical Research
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-04-02
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Over 6 months from beginning of treatment
Secondary outcomes:
measure: Serum Total Tryptase
timeFrame: 6 months after start of treatment
measure: Bronchoalveolar Lavage (BAL) Fluid Tryptase Level
timeFrame: 6 months after start of treatment
measure: Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) %
timeFrame: 6 months after start of treatment
measure: Number of Asthma Exacerbations
timeFrame: Up to 24 weeks
measure: FEV1 in Liters
timeFrame: 6 months after start of treatment
measure: FEV1%
timeFrame: 6 months after start of treatment
measure: Morning Peak Flow Measurement
timeFrame: 6 months after start of treatment
measure: Evening Peak Flow
timeFrame: 6 months after start of treatment
measure: Fractional Exhaled Nitric Oxide (FeNO)
timeFrame: 6 months after start of treatment
measure: Asthma Control Questionnaire (ACQ)
timeFrame: 6 months after start of treatment
measure: Asthma Quality of Life Questionnaire (AQLQ)
timeFrame: 6 months after start of treatment
measure: Asthma Symptom Utility Index (ASUI)
timeFrame: 6 months after start of treatment
measure: BAL Neutrophil %
timeFrame: 6 months after start of treatment
measure: BAL Eosinophil %
timeFrame: 6 months after start of treatment
measure: Bronchoalveolar Lavage (BAL) PGD2
timeFrame: 6 months after start of treatment
measure: Endobronchial Biopsy Total Tryptase-positive Mast Cells
timeFrame: 6 months after start of treatment
measure: Endobronchial Biopsy Smooth Muscle Tryptase-positive Mast Cells
timeFrame: 6 months after start of treatment
measure: Blood Eosinophils
timeFrame: 6 months after start of treatment
measure: Airway Wall Thickness
timeFrame: 6 months after start of treatment
measure: Airway Wall Area
timeFrame: 6 months after start of treatment
measure: Bronchoalveolar Lavage Histamine
timeFrame: 6 months after start of treatment
measure: Urinary Prostaglandin D2
timeFrame: 6 months after start of treatment
measure: Bronchoalveolar Lavage Cysteinyl Leukotrienes
timeFrame: 6 months after start of treatment
measure: Urinary Leukotriene E4
timeFrame: 6 months after start of treatment
measure: Change in Sputum Supernatant Differential, Supernatant Tryptase and IL-13
timeFrame: baseline to 24 weeks
measure: Change in Inflammatory Mediators in Exhaled Breath Condensate
timeFrame: baseline to week 24
measure: Change in Number of Self-Reported Asthma Symptom Free Days
timeFrame: baseline to week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Brigham and Womens Hospital
name: Elliot Israel, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Womens Hospital
name: Joshua Boyce, M.D
role: PRINCIPAL_INVESTIGATOR
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