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AsthmaPhase 2KIANCT01097694

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

A Phase 2 study testing Imatinib mesylate in people with Asthma, run by Brigham and Women's Hospital at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Asthma
What is being tested?
Imatinib mesylate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
176 participants
Where
7 sitesUnited States
Study dates
Nov 2010to Aug 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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
Show all 14Show fewer
  • 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

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • University of Alabama

    Birmingham, Alabama, 35294

  • Brigham and Womens Hospital

    Boston, Massachusetts, 02115

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • University of Wisconsin

    Madison, Wisconsin, 53792

  • Columbia University

    New York, New York, 10032

  • Temple University

    Philadelphia, Pennsylvania, 19140

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

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)

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.

Read the 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.

Conditions
Asthma
Being tested
Imatinib mesylate, Placebo
Keywords
cKIT inhibition in Asthma, Efficacy of Imatinib in severe resistent asthma.
Medical subject headings
Asthma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Imatinib mesylateDrug

    Also called 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.

  • PlaceboDrug

    Placebo

Study groups in NCT01097694
Study groupRoleWhat they receive
Imatinib mesylateActive comparatorGroup on active imatinib treatment
Receives: Drug: Imatinib mesylate
PlaceboPlacebo comparatorGroup on Placebo treatment
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: Over 6 months from beginning of treatment

Secondary outcomes (27)

  1. Serum Total Tryptase

    Change in serum total tryptase after 24 weeks of imatinib vs placebo treatment

    Measured: 6 months after start of treatment

  2. Bronchoalveolar Lavage (BAL) Fluid Tryptase Level

    Change in BAL fluid tryptase levels after 24 weeks of imatinib vs. placebo

    Measured: 6 months after start of treatment

  3. Change in Maximum Post-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) %

    Measured: 6 months after start of treatment

  4. Number of Asthma Exacerbations

    Number of asthma exacerbations experienced from randomization to study completion.

    Measured: Up to 24 weeks

  5. FEV1 in Liters

    Change in FEV1 in treatment group compared to placebo group

    Measured: 6 months after start of treatment

  6. FEV1%

    Change in FEV1% of predicted

    Measured: 6 months after start of treatment

  7. Morning Peak Flow Measurement

    Change in patient-reported morning peak flow measurement (L/s)

    Measured: 6 months after start of treatment

  8. Evening Peak Flow

    Change in patient-reported evening peak flow measurement (L/s)

    Measured: 6 months after start of treatment

  9. Fractional Exhaled Nitric Oxide (FeNO)

    Change in Fractional Exhaled Nitric Oxide Measurement (ppb)

    Measured: 6 months after start of treatment

  10. 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.

    Measured: 6 months after start of treatment

  11. 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.

    Measured: 6 months after start of treatment

  12. 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.

    Measured: 6 months after start of treatment

  13. BAL Neutrophil %

    Change in BAL neutrophil percentage from baseline

    Measured: 6 months after start of treatment

  14. BAL Eosinophil %

    Change in BAL eosinophil percentage

    Measured: 6 months after start of treatment

  15. Bronchoalveolar Lavage (BAL) PGD2

    Change in bronchoalveolar lavage (BAL) PGD2 levels from baseline at 6 months

    Measured: 6 months after start of treatment

  16. Endobronchial Biopsy Total Tryptase-positive Mast Cells

    Change in endobronchial biopsy total tryptase-positive mast cells from baseline at 6 months

    Measured: 6 months after start of treatment

  17. Endobronchial Biopsy Smooth Muscle Tryptase-positive Mast Cells

    Change in the biopsy smooth muscle tryptase-positive mast cells from baseline at 6 months

    Measured: 6 months after start of treatment

  18. Blood Eosinophils

    Change in blood eosinophil count

    Measured: 6 months after start of treatment

  19. Airway Wall Thickness

    Change in airway wall thickness as assessed by computerized tomography (CT)

    Measured: 6 months after start of treatment

  20. Airway Wall Area

    Change in airway wall area as assessed by computerized tomography (CT)

    Measured: 6 months after start of treatment

  21. Bronchoalveolar Lavage Histamine

    Change in bronchoalveolar lavage histamine levels from baseline

    Measured: 6 months after start of treatment

  22. Urinary Prostaglandin D2

    Change in urinary Prostaglandin D2 levels from baseline

    Measured: 6 months after start of treatment

  23. Bronchoalveolar Lavage Cysteinyl Leukotrienes

    Change in bronchoalveolar lavage cysteinyl leukotrienes levels from baseline

    Measured: 6 months after start of treatment

  24. Urinary Leukotriene E4

    Change in urinary leukotriene E4 levels from baseline

    Measured: 6 months after start of treatment

  25. 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.

    Measured: baseline to 24 weeks

  26. Change in Inflammatory Mediators in Exhaled Breath Condensate

    Assessment of change in eicosanoids in the exhaled breath condensate

    Measured: baseline to week 24

  27. Change in Number of Self-Reported Asthma Symptom Free Days

    Measured: baseline to week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Apr 2010 (estimated)
  2. Study startNov 2010
  3. Primary completionAug 2015
  4. Study completionAug 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
176 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01097694
Sponsor's protocol ID
2010P000170
Other IDs
U01HL102225
Acronym
KIA
Status last verified
May 2017
First submitted
23 Mar 2010
Last updated
19 May 2017
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 15196279

  • 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.

    PubMed 1370529

  • 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.

    PubMed 12037149

  • 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.

    PubMed 10233863

  • 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.

    PubMed 12149526

  • 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.

    PubMed 17872493

  • 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.

    PubMed 11112161

  • 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.

    PubMed 8630386

  • 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.

    PubMed 19264687

  • 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.

    PubMed 16483568

  • 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.

    PubMed 9221761

  • 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.

    PubMed 28514613

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Imatinib mesylate in people with Asthma, run by Brigham and Women's Hospital at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01097694, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2017.

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