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

NCT01097694 | Completed Phase 2 Results DMC

• 2 other identifiers: 2010P000170U01HL102225
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 7

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.

Conditions

Asthma

Keywords

cKIT inhibition in Asthma; Efficacy of Imatinib in severe resistent asthma.

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (27)

• Serum Total Tryptase

  6 months after start of treatment

• Bronchoalveolar Lavage (BAL) Fluid Tryptase Level

  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

  Up to 24 weeks

• FEV1 in Liters

  6 months after start of treatment

Study Arms (2)

Imatinib mesylate

ACTIVE COMPARATOR

Group on active imatinib treatment

Drug: Imatinib mesylate

Placebo

PLACEBO COMPARATOR

Group on Placebo treatment

Drug: Placebo

Interventions

Imatinib mesylate DRUG

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.

Also known as: Gleevec, Zoleta, Glivec, Ziatir

Imatinib mesylate

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Baim Institute for Clinical Research: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (7)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

Brigham and Womens Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Temple University

Philadelphia, Pennsylvania, 19140, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (12)

• 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.

  PMID: 15196279 BACKGROUND

• 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.

  PMID: 1370529 BACKGROUND

• 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.

  PMID: 12037149 BACKGROUND

• 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.

  PMID: 10233863 BACKGROUND

• 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.

  PMID: 12149526 BACKGROUND

• 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.

  PMID: 17872493 BACKGROUND

• 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.

  PMID: 11112161 BACKGROUND

• 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.

  PMID: 8630386 BACKGROUND

• 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.

  PMID: 19264687 BACKGROUND

• 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.

  PMID: 16483568 BACKGROUND

• 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.

  PMID: 9221761 BACKGROUND

• 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.

  PMID: 28514613 DERIVED

MeSH Terms

Conditions

Asthma

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Results Point of Contact

• Title: Elliot Israel, MD
• Organization: Brigham and Women's Hopsital

eisrael@partners.org

617-732-8110

Study Officials

• Elliot Israel, M.D

  Brigham and Womens Hospital

  PRINCIPAL INVESTIGATOR

• Joshua Boyce, M.D

  Brigham and Womens Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Asthma Research Center

Study Record Dates

• First Submitted: March 23, 2010
• First Posted: April 2, 2010
• Study Start: November 1, 2010
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2016
• Last Updated: May 19, 2017
• Results First Posted: May 19, 2017

Record last verified: 2017-05

Locations

US (7)