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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01097694
First Posted: April 2, 2010
Last Update Posted: May 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Baim Institute for Clinical Research
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Elliot Israel, MD, Brigham and Women's Hospital
  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
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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 Elliot Israel, MD, Brigham and Women's Hospital:

Primary Outcome Measures:
  • 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 [ Time Frame: 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:
  • Serum Total Tryptase [ Time Frame: 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 [ Time Frame: 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) % [ Time Frame: 6 months after start of treatment ]
  • Number of Asthma Exacerbations [ Time Frame: Up to 24 weeks ]
    Number of asthma exacerbations experienced from randomization to study completion.

  • FEV1 in Liters [ Time Frame: 6 months after start of treatment ]
    Change in FEV1 in treatment group compared to placebo group

  • FEV1% [ Time Frame: 6 months after start of treatment ]
    Change in FEV1% of predicted

  • Morning Peak Flow Measurement [ Time Frame: 6 months after start of treatment ]
    Change in patient-reported morning peak flow measurement (L/s)

  • Evening Peak Flow [ Time Frame: 6 months after start of treatment ]
    Change in patient-reported evening peak flow measurement (L/s)

  • Fractional Exhaled Nitric Oxide (FeNO) [ Time Frame: 6 months after start of treatment ]
    Change in Fractional Exhaled Nitric Oxide Measurement (ppb)

  • Asthma Control Questionnaire (ACQ) [ Time Frame: 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.

  • Asthma Quality of Life Questionnaire (AQLQ) [ Time Frame: 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) [ Time Frame: 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 % [ Time Frame: 6 months after start of treatment ]
    Change in BAL neutrophil percentage from baseline

  • BAL Eosinophil % [ Time Frame: 6 months after start of treatment ]
    Change in BAL eosinophil percentage

  • Bronchoalveolar Lavage (BAL) PGD2 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 6 months after start of treatment ]
    Change in the biopsy smooth muscle tryptase-positive mast cells from baseline at 6 months

  • Blood Eosinophils [ Time Frame: 6 months after start of treatment ]
    Change in blood eosinophil count

  • Airway Wall Thickness [ Time Frame: 6 months after start of treatment ]
    Change in airway wall thickness as assessed by computerized tomography (CT)

  • Airway Wall Area [ Time Frame: 6 months after start of treatment ]
    Change in airway wall area as assessed by computerized tomography (CT)

  • Bronchoalveolar Lavage Histamine [ Time Frame: 6 months after start of treatment ]
    Change in bronchoalveolar lavage histamine levels from baseline

  • Urinary Prostaglandin D2 [ Time Frame: 6 months after start of treatment ]
    Change in urinary Prostaglandin D2 levels from baseline

  • Bronchoalveolar Lavage Cysteinyl Leukotrienes [ Time Frame: 6 months after start of treatment ]
    Change in bronchoalveolar lavage cysteinyl leukotrienes levels from baseline

  • Urinary Leukotriene E4 [ Time Frame: 6 months after start of treatment ]
    Change in urinary leukotriene E4 levels from baseline

  • Change in Sputum Supernatant Differential, Supernatant Tryptase and IL-13 [ Time Frame: 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 [ Time Frame: baseline to week 24 ]
    Assessment of change in eicosanoids in the exhaled breath condensate

  • Change in Number of Self-Reported Asthma Symptom Free Days [ Time Frame: baseline to week 24 ]

Enrollment: 176
Study Start Date: November 2010
Study Completion Date: August 2016
Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Imatinib mesylate
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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01097694


Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, Massachusetts
Brigham and Womens Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Temple University
Philadelphia, Pennsylvania, United States, 19140
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Brigham and Women's Hospital
Baim Institute for Clinical Research
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Elliot Israel, M.D Brigham and Womens Hospital
Principal Investigator: Joshua Boyce, M.D Brigham and Womens Hospital
  More Information

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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 ( U.S. NIH Grant/Contract )
First Submitted: March 23, 2010
First Posted: April 2, 2010
Results First Submitted: April 4, 2017
Results First Posted: May 19, 2017
Last Update Posted: May 19, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Elliot Israel, MD, 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 Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action