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

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)

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo; Drug: Imatinib mesylate

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.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Womens Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Gleevec, Zoleta, Glivec, Ziatir
Placebo Comparator: Placebo; Group on Placebo treatment	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	Over 6 months from beginning of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Total Tryptase	Change in serum total tryptase after 24 weeks of imatinib vs placebo treatment	6 months after start of treatment
Bronchoalveolar Lavage (BAL) Fluid Tryptase Level	Change in BAL fluid tryptase levels after 24 weeks of imatinib vs. placebo	6 months after start of treatment
Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) %		6 months after start of treatment
Number of Asthma Exacerbations	Number of asthma exacerbations experienced from randomization to study completion.	Up to 24 weeks
FEV1 in Liters	Change in FEV1 in treatment group compared to placebo group	6 months after start of treatment
FEV1%	Change in FEV1% of predicted	6 months after start of treatment
Morning Peak Flow Measurement	Change in patient-reported morning peak flow measurement (L/s)	6 months after start of treatment
Evening Peak Flow	Change in patient-reported evening peak flow measurement (L/s)	6 months after start of treatment
Fractional Exhaled Nitric Oxide (FeNO)	Change in Fractional Exhaled Nitric Oxide Measurement (ppb)	6 months after start of treatment
Asthma Control Questionnaire (ACQ)	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.	6 months after start of treatment
Asthma Quality of Life Questionnaire (AQLQ)	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.	6 months after start of treatment
Asthma Symptom Utility Index (ASUI)	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.	6 months after start of treatment
BAL Neutrophil %	Change in BAL neutrophil percentage from baseline	6 months after start of treatment
BAL Eosinophil %	Change in BAL eosinophil percentage	6 months after start of treatment
Bronchoalveolar Lavage (BAL) PGD2	Change in bronchoalveolar lavage (BAL) PGD2 levels from baseline at 6 months	6 months after start of treatment
Endobronchial Biopsy Total Tryptase-positive Mast Cells	Change in endobronchial biopsy total tryptase-positive mast cells from baseline at 6 months	6 months after start of treatment
Endobronchial Biopsy Smooth Muscle Tryptase-positive Mast Cells	Change in the biopsy smooth muscle tryptase-positive mast cells from baseline at 6 months	6 months after start of treatment
Blood Eosinophils	Change in blood eosinophil count	6 months after start of treatment
Airway Wall Thickness	Change in airway wall thickness as assessed by computerized tomography (CT)	6 months after start of treatment
Airway Wall Area	Change in airway wall area as assessed by computerized tomography (CT)	6 months after start of treatment
Bronchoalveolar Lavage Histamine	Change in bronchoalveolar lavage histamine levels from baseline	6 months after start of treatment
Urinary Prostaglandin D2	Change in urinary Prostaglandin D2 levels from baseline	6 months after start of treatment
Bronchoalveolar Lavage Cysteinyl Leukotrienes	Change in bronchoalveolar lavage cysteinyl leukotrienes levels from baseline	6 months after start of treatment
Urinary Leukotriene E4	Change in urinary leukotriene E4 levels from baseline	6 months after start of treatment
Change in Sputum Supernatant Differential, Supernatant Tryptase and IL-13	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.	baseline to 24 weeks
Change in Inflammatory Mediators in Exhaled Breath Condensate	Assessment of change in eicosanoids in the exhaled breath condensate	baseline to week 24
Change in Number of Self-Reported Asthma Symptom Free Days		baseline to week 24

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Baim Institute for Clinical Research
• Investigators: Principal Investigator: Joshua Boyce, M.D, Brigham and Womens Hospital

Publications and helpful links

General Publications

• Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985-93. doi: 10.1056/NEJMoa0805435.
• Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000 Dec;162(6):2341-51. doi: 10.1164/ajrccm.162.6.ats9-00. No abstract available.
• Al-Muhsen SZ, Shablovsky G, Olivenstein R, Mazer B, Hamid Q. The expression of stem cell factor and c-kit receptor in human asthmatic airways. Clin Exp Allergy. 2004 Jun;34(6):911-6. doi: 10.1111/j.1365-2222.2004.01975.x.
• Bischoff SC, Dahinden CA. c-kit ligand: a unique potentiator of mediator release by human lung mast cells. J Exp Med. 1992 Jan 1;175(1):237-44. doi: 10.1084/jem.175.1.237.
• Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002 May 30;346(22):1699-705. doi: 10.1056/NEJMoa012705.
• Campbell E, Hogaboam C, Lincoln P, Lukacs NW. Stem cell factor-induced airway hyperreactivity in allergic and normal mice. Am J Pathol. 1999 Apr;154(4):1259-65. doi: 10.1016/S0002-9440(10)65377-1.
• Carroll NG, Mutavdzic S, James AL. Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax. 2002 Aug;57(8):677-82. doi: 10.1136/thorax.57.8.677.
• Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, Barnes NC; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1062-71. doi: 10.1164/rccm.200701-085OC. Epub 2007 Sep 13.
• Lukacs NW, Kunkel SL, Strieter RM, Evanoff HL, Kunkel RG, Key ML, Taub DD. The role of stem cell factor (c-kit ligand) and inflammatory cytokines in pulmonary mast cell activation. Blood. 1996 Mar 15;87(6):2262-8.
• Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 2006 Mar 8;533(1-3):327-40. doi: 10.1016/j.ejphar.2005.12.067. Epub 2006 Feb 17.
• Yuan Q, Austen KF, Friend DS, Heidtman M, Boyce JA. Human peripheral blood eosinophils express a functional c-kit receptor for stem cell factor that stimulates very late antigen 4 (VLA-4)-mediated cell adhesion to fibronectin and vascular cell adhesion molecule 1 (VCAM-1). J Exp Med. 1997 Jul 21;186(2):313-23. doi: 10.1084/jem.186.2.313.
• Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 10.1056/NEJMoa1613125.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: March 23, 2010
• First Submitted That Met QC Criteria: March 31, 2010
• First Posted (Estimate): April 2, 2010

Study Record Updates

• Last Update Posted (Actual): May 19, 2017
• Last Update Submitted That Met QC Criteria: May 15, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: cKIT inhibition in Asthma; Efficacy of Imatinib in severe resistent asthma.
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 2010P000170; U01HL102225 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED