Clinical trial NCT00656058
Conditions: Bronchiolitis Obliterans Chronic Graft Versus Host Disease Leukotriene Montelukast Stem Cell Transplant
Keywords: Leukotriene Chronic Graft-Versus-Host Disease Montelukast Stem Cell Transplant Bronchiolitis Obliterans
Sponsor: National Cancer Institute (NCI)
Start date: 2008-06-17; Completion date: 2018-02-22
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Bronchiolitis obliterans is a form of chronic graft-versus-host disease (GVHD) that sometimes develops after stem cell transplantation (SCT) or bone marrow transplantation (BMT).

In bronchiolitis obliterans, immune cells that normally fight infections attack the lungs of the transplant recipient, causing destruction of lung tissue and fibrosis (scarring). When fibrosis develops, the lungs cannot work properly.

Montelukast (Singulair) is a drug that has been used for many years to treat asthma. Its use as a treatment for bronchiolitis obliterans is experimental.

Objectives:

To see if montelukast improves or stabilizes lung function in patients who develop bronchiolitis obliterans after BMT or SCT.

To assess the safety of montelukast in patients with bronchiolitis obliterans after BMT or SCT

To see if montelukast affects the cells that damage the lungs.

To see if montelukast improves other forms of chronic GVHD, quality of life, and overall survival in patients with bronchiolitis obliterans after BMT or SCT.

Eligibility:

Patients 6 years of age and older with bronchiolitis obliterans following stem cell transplantation.

Design:

Patients take one montelukast tablet daily for 6 months and undergo the following procedures during this period:

* Lung function tests. The patient breathes into a machine that measures the amount of air that goes into and out of the lungs. This test is done once a month for 3 months, then at 6 months, 12 months and 24 months.
* Medical history and physical examination at the study site about every 3 months for the first year of the study and then at 12 months and 24 months. Patients also have physical examinations monthly for the first 6 months at their primary doctors office. Tests may include blood and urine tests, chest computed tomography (CT) scans, echocardiogram (heart ultrasound), 2- and 6-minute walk tests, and quality-of-life questionnaires.
* Bronchoalveolar lavage in patients 18 years of age and older. The subject s mouth, nose and airways are numbed with lidocaine. Some patients may need sedation or anesthesia for the procedure. A tube (bronchoscope) is then passed through the nose into the airway, and a small amount of fluid is put into the lung. The fluid is then removed and tested for infections or other lung problems.
* Apheresis to collect white blood cells. Whole blood is collected through a tube inserted into a vein in the arm. The white cells are extracted in a cell separator machine, and the rest of the blood is returned to the body through a tube placed in a vein in the other arm. The cells are used to study GVHD and bronchiolitis obliterans.
* Patients who wish to continue montelukast therapy after 6 months may do so under the care of their primary doctor, if both agree to the continuation....

Detailed description:
Background:

Bronchiolitis obliterans (BO) is an insidious disease with high mortality following allogeneic blood or marrow transplantation (BMT). There are no consistently effective treatments for BO following BMT and the pathogenesis is largely unknown.

The mechanisms underlying similar immune-mediated lung destructive processes are better elucidated. Rejection following allogeneic lung transplantation and scleroderma lung disease result from analogous immunologically mediated destruction of lung tissue leading to similar pathologic and clinical presentations to post-BMT BO.

Increased leukotriene production has recently been implicated in the development of both post-lung transplant BO and scleroderma lung disease in animal models and patient studies.

Montelukast (singulair) is an approved, well-tolerated, oral agent that inhibits leukotriene action in lung inflammation. This agent has been extensively used in children and adults to treat asthma with an excellent safety profile.

Objectives:

To evaluate if montelukast stabilizes or improves pulmonary function in patients with BO after BMT using forced expiratory volume 1 (FEV-1) changes as primary endpoints, and oxygen saturation, pulmonary function test (PFT) parameters (forced expiratory flow (FEF) 25-75, residual volume (RV) and RV/forced vital capacity (FVC), carbon monoxide diffusing capacity (DLC02), FEV-1/FVC, FEV-1/slow vital capacity (SVC) ratio), and timed walk tests as secondary endpoints.

To evaluate the safety of montelukast in the population of patients with BO after BMT.

To investigate if leukotriene elevation contributes to the pathogenesis of BO after BMT by measuring leukotriene levels of the blood, urine, and bronchoalveolar lavage (BAL), and leukotriene surface receptor expression on immune cells before and after montelukast administration.

To determine if montelukast improves other chronic graft versus host disease (cGVHD) manifestations, quality of life, and overall survival.

Eligibility:

Patients greater than or equal to 6 years old with bronchiolitis obliterans following stem cell transplantation for any disease indication may be enrolled.

Design:

This is a prospective phase II study, the primary aim of which is to assess whether montelukast improves or stabilizes the pulmonary function of patients with BO after BMT.

Primary outcome data will be analyzed in 2 ways. 1) The proportion of patients with stable or improved percent predicted of FEV-1 will be compared against benchmark data obtained from a literature review. 2) The slope of FEV-1 before and after the introduction of montelukast will be compared.

Pediatric and adult patients with BO following BMT will receive approved doses of montelukast continuously.

The planned length of the study would be 2 years per patient with primary endpoint at 6 months, permitting sufficient time to determine safety and meet other endpoints.

This phase II trial will be conducted at 2 institutions: National Institutes of Health (NIH) and Fred Hutchinson Cancer Research Center. Forty-five patients will be enrolled on this trial.

Arms: arm 1: Montelukast for the treatment of BO following allogeneic or autologous stem cell transplant.
Interventions: intervention 1: Singulair (Montelukast Sodium)
Intervention descriptions: intervention 1: Singulair (Montelukast Sodium):5-10 mg (weight based dosing) by mouth (PO) hour of sleep (HS)

Protocol documents:
Prot_ICF_000.pdf: 
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PRECIS ................................................................................................................................................ 4 
7DEOHRI&RQWHQWV ................................................................................................................................. 5 
1 
Introduction .................................................................................................................................. 7 
1.1 
Study Objectives ...............................................................................................................................7 
1.2 
Background and Rationale ..............................................................................................................7 
2 
Eligibility Assessment and Enrollment ..................................................................................... 13 
2.1 
Eligibility Criteria ..........................................................................................................................13 
2.2 
Research Eligibility Evaluation (See Appendix 2) .......................................................................16 
2.3 
Registration Procedure: .................................................................................................................16 
3 
Study Implementation ................................................................................................................ 17 
3.1 
Study Design ....................................................................................................................................17 
3.2 
Drug Administration ......................................................................................................................18 
3.3 
Treatment Modifications ...............................................................................................................18 
3.4 
On Study Protocol Evaluation: Appendix 2 A/B .........................................................................19 
3.5 
Concurrent Therapy for Chronic Graft versus Host Disease: ...................................................24 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria: .....................................26 
3.7 
Off- Protocol Therapy, Off-Study, and Post-protocol therapy Evaluation (Appendix 2A) .....27 
4 
Supportive Care Guidelines ....................................................................................................... 28 
5 
Data Collection and Evaluation ................................................................................................ 29 
5.1 
Data Collection ................................................................................................................................29 
5.2 
Response Criteria: ..........................................................................................................................30 
5.3 
Toxicity Criteria .............................................................................................................................32 
5.4 
Statistical Considerations...............................................................................................................32 
5.5 
Multi-Institutional Guidelines: ......................................................................................................35 
6 
Human Subjects Protections ..................................................................................................... 36 
6.1 
Rationale for patient selection .......................................................................................................36 
6.2 
Participation of Children ...............................................................................................................36 
6.3 
NCI PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ..............................36 
6.4 
Evaluation of Benefits and Risks/Discomforts: ............................................................................37 
6.5 
Risk/Benefit Analysis ......................................................................................................................37 
6.6 
Consent and Assent Process and Documentation ........................................................................38 
7 
Safety Reporting Requirements and Safety Monitoring Plan .................................................. 39 


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7.1 
Definitions .......................................................................................................................................39 
7.2 
NCI-IRB and NCI Clinical Director Reporting ...........................................................................41 
7.3 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ..................42 
7.4 
Data and Safety Monitoring Plan ..................................................................................................43 
7.5 
Abnormal Laboratory Test Results ..............................................................................................43 
7.6 
Withdrawal from Study .................................................................................................................44 
8 
Pharmaceutical Drug Information ........................................................................................... 44 
8.1 
Montelukast (Singulair) .................................................................................................................44 
9 
References: ................................................................................................................................. 47 
10 Appendices .................................................................................................................................. 51 
10.1 
Appendix 1: Performance Scales ...................................................................................................51 
10.2 
Appendix 2A: Required Study Evaluations .................................................................................52 
10.3 
APPENDIX 2B ................................................................................................................................54 
10.4 
Appendix 3: Initial History Guidelines .........................................................................................55 
10.5 
Appendix 4: Chronic GVHD Activity Assessment- Clinician ....................................................57 
10.6 
Appendix 5A: Sign and symptoms of cGVHD .............................................................................61 
10.7 
Appendix 5B: Core set of measures for assessing responses in chronic GVHD trials .............63 
10.8 
Appendix 6: cGVHD score sheet ...................................................................................................64 
10.9 
Appendix 7: Chronic GVHD Manifestations ...............................................................................66 
10.10 Appendix 8: Lung Function Score ................................................................................................67 
10.11 Appendix 9: Physiatry Evaluation: ...............................................................................................68 
10.12 Appendix 10: Chronic GVHD patient symptom scale ................................................................69 
10.13 Appendix 11: Patient Diary for Montelukast (Singulair) ...........................................................70 
10.14 Appendix 12: Chronic GVHD Activity Assessment- Patient Self Report .................................72 
10.15 Appendix 13: QOL and Functional assessment scales ................................................................74 
10.16 Appendix 14: ETIB Policy for Sample Handling.........................................................................76 
10.17 Appendix 15: NIH Problem Report Form....................................................................................80 
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