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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Brigham and Women's Hospital
Sponsor:
Collaborators:
Harvard Clinical Research Institute
Information provided by (Responsible Party):
Elliot Israel, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT01097694
First received: March 23, 2010
Last updated: July 16, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Asthma
Drug: Imatinib mesylate
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • Methacholine responsiveness [ Time Frame: At visit 2, 12 and 16 ( 2 weeks before starting therapy and after 13 and 23 weeks of starting therapy ] [ Designated as safety issue: No ]
    Primary outcome of this study is the change in methacholine responsiveness from baseline to 6 months of therapy in imatinib treated patients as compared with controls


Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    Changes in airway mast cell populations and phenotype after 24 weeks of imatinib therapy.


Estimated Enrollment: 180
Study Start Date: November 2010
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Imatinib treatment
Group on active imatinib treatment
Drug: Imatinib mesylate
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.
Other Name: Gleevec, Zoleta, Glivec, Ziatir
Placebo Comparator: Placebo
Group on Placebo treatment
Drug: Placebo
Placebo

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

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01097694

Contacts
Contact: Allison Crosy-Thompson 617-525-8034 acrosby-thompson@partners.org

Locations
United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35294
Contact: Necole Harris    205-934-9240    Necole.Harris@ccc.uab.edu   
Principal Investigator: Mark Dransfield, M.D.         
Sub-Investigator: Jennifer L Trevor, M.D.         
United States, Massachusetts
Brigham and Womens Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Allison Crosby-Thompson, M.S.    617-525-8034    acrosby-thompson@partners.org   
Contact: Robert Pedicini, B.S.    617-732-8112    rpedicini@partners.org   
Principal Investigator: Elliot Israel, M.D.         
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Vanessa Curtis    314-454-8776    vcurtis@dom.wustl.edu   
Contact: Terri Radake    314-362-8892    radaket@dom.wustl.edu   
Principal Investigator: Mario Castro, M.D         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Surinder Narula    212-305-0251    sn2027@columbia.edu   
Principal Investigator: Emily DiMango, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Jackie Sharp       pylej@ccf.org   
Contact: Michelle Koo    216-445-6696    KOOM@ccf.org   
Principal Investigator: Serpil Erzurum, MD         
United States, Pennsylvania
Temple University Recruiting
Philadelphia, Pennsylvania, United States, 19140
Contact: Denean Allen    215-707-8129    Denean.Allen@tuhs.temple.edu   
Principal Investigator: Kartik Shenoy, M.D.         
United States, Wisconsin
University of Wisconsin Recruiting
Madison, Wisconsin, United States, 53792
Contact: Gina Crisafi    608-265-4554    gmc@medicine.wisc.edu   
Principal Investigator: Nizar Jarjour, M.D         
Sponsors and Collaborators
Brigham and Women's Hospital
Harvard Clinical Research Institute
Investigators
Principal Investigator: Elliot Israel, M.D Brigham and Womens Hospital
Principal Investigator: Joshua Boyce, M.D Brigham and Womens Hospital
  More Information

Publications:

Responsible Party: Elliot Israel, MD, Director of the Asthma Research Center, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01097694     History of Changes
Other Study ID Numbers: 2010P000170, U01HL102225
Study First Received: March 23, 2010
Last Updated: July 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Brigham and Women's Hospital:
cKIT inhibition in Asthma
Efficacy of Imatinib in severe resistent asthma.

Additional relevant MeSH terms:
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014