Overview

This trial is active, not recruiting.

Condition asthma
Treatments imatinib mesylate, placebo
Phase phase 2
Targets KIT, PDGF, BCR-ABL
Sponsor Brigham and Women's Hospital
Collaborator Harvard Clinical Research Institute
Start date November 2010
End date August 2015
Trial size 180 participants
Trial identifier NCT01097694, 2010P000170, U01HL102225

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Active Comparator)
Group on active imatinib treatment
imatinib mesylate Gleevec, Zoleta, Glivec, Ziatir
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 Comparator)
Group on Placebo treatment
placebo
Placebo

Primary Outcomes

Measure
Methacholine responsiveness
time frame: At visit 2, 12 and 16 ( 2 weeks before starting therapy and after 13 and 23 weeks of starting therapy

Secondary Outcomes

Measure
Change in airway mast cell populations and phenotype.
time frame: Visit 4, 11 and 17 (2 days before starting treatment and at 12 and 23 weeks after starting treatment)

Eligibility Criteria

Male or female participants from 18 years up to 65 years old.

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

Additional Information

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)
Principal investigator Elliot Israel, M.D
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.
Trial information was received from ClinicalTrials.gov and was last updated in June 2016.
Information provided to ClinicalTrials.gov by Brigham and Women's Hospital.