Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)
- Registration Number
- NCT01097694
- Lead Sponsor
- Brigham and Women's Hospital
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 176
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Imatinib mesylate Imatinib mesylate Group on active imatinib treatment Placebo Placebo Group on Placebo treatment
- Primary Outcome Measures
Name Time Method 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 Over 6 months from beginning of treatment 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).
- Secondary Outcome Measures
Name Time Method Serum Total Tryptase 6 months after start of treatment Change in serum total tryptase after 24 weeks of imatinib vs placebo treatment
Bronchoalveolar Lavage (BAL) Fluid Tryptase Level 6 months after start of treatment Change in BAL fluid tryptase levels after 24 weeks of imatinib vs. placebo
Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) % 6 months after start of treatment Number of Asthma Exacerbations Up to 24 weeks Number of asthma exacerbations experienced from randomization to study completion.
FEV1 in Liters 6 months after start of treatment Change in FEV1 in treatment group compared to placebo group
FEV1% 6 months after start of treatment Change in FEV1% of predicted
Morning Peak Flow Measurement 6 months after start of treatment Change in patient-reported morning peak flow measurement (L/s)
Evening Peak Flow 6 months after start of treatment Change in patient-reported evening peak flow measurement (L/s)
Fractional Exhaled Nitric Oxide (FeNO) 6 months after start of treatment Change in Fractional Exhaled Nitric Oxide Measurement (ppb)
Asthma Control Questionnaire (ACQ) 6 months after start of treatment 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.
Airway Wall Area 6 months after start of treatment Change in airway wall area as assessed by computerized tomography (CT)
Bronchoalveolar Lavage Histamine 6 months after start of treatment Change in bronchoalveolar lavage histamine levels from baseline
Asthma Quality of Life Questionnaire (AQLQ) 6 months after start of treatment 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.
Asthma Symptom Utility Index (ASUI) 6 months after start of treatment 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.
BAL Neutrophil % 6 months after start of treatment Change in BAL neutrophil percentage from baseline
BAL Eosinophil % 6 months after start of treatment Change in BAL eosinophil percentage
Bronchoalveolar Lavage (BAL) PGD2 6 months after start of treatment Change in bronchoalveolar lavage (BAL) PGD2 levels from baseline at 6 months
Endobronchial Biopsy Total Tryptase-positive Mast Cells 6 months after start of treatment Change in endobronchial biopsy total tryptase-positive mast cells from baseline at 6 months
Endobronchial Biopsy Smooth Muscle Tryptase-positive Mast Cells 6 months after start of treatment Change in the biopsy smooth muscle tryptase-positive mast cells from baseline at 6 months
Blood Eosinophils 6 months after start of treatment Change in blood eosinophil count
Airway Wall Thickness 6 months after start of treatment Change in airway wall thickness as assessed by computerized tomography (CT)
Urinary Prostaglandin D2 6 months after start of treatment Change in urinary Prostaglandin D2 levels from baseline
Bronchoalveolar Lavage Cysteinyl Leukotrienes 6 months after start of treatment Change in bronchoalveolar lavage cysteinyl leukotrienes levels from baseline
Urinary Leukotriene E4 6 months after start of treatment Change in urinary leukotriene E4 levels from baseline
Change in Sputum Supernatant Differential, Supernatant Tryptase and IL-13 baseline to 24 weeks 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.
Change in Inflammatory Mediators in Exhaled Breath Condensate baseline to week 24 Assessment of change in eicosanoids in the exhaled breath condensate
Change in Number of Self-Reported Asthma Symptom Free Days baseline to week 24
Trial Locations
- Locations (7)
University of Alabama
🇺🇸Birmingham, Alabama, United States
Columbia University
🇺🇸New York, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Temple University
🇺🇸Philadelphia, Pennsylvania, United States
Brigham and Womens Hospital
🇺🇸Boston, Massachusetts, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States