Montelukast to Treat Bronchiolitis Obliterans
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.
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.
Patients 6 years of age and older with bronchiolitis obliterans following stem cell transplantation.
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 doctor s office. Tests may include blood and urine tests, chest 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....
Chronic Graft Versus Host Disease
Stem Cell Transplant
Drug: Montelukast sodium
Other: Flow cytometry
Other: Laboratory biomarker analysis
Procedure: Quality-of-life assessment
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Multi-Institutional Prospective Phase II Study of Montelukast for the Treatment of Bronchiolitis Obliterans Following Allogeneic or Autologous Stem Cell Transplantation in Children and Adults|
- Comparison of the proportion of patients with stable or improved percentage or predeicted FEV1 with published literature. [ Designated as safety issue: No ]
- Comparison of the slope of FEV1 before and after treatment with montelukast sodium [ Designated as safety issue: No ]
- Oxygen saturation and supplementation [ Designated as safety issue: No ]
- Pulmonary function tests, including FEF25-75, RV or RV/FVC, DLC02, and the ratio of FEV1/FVC and FEV1/SVC [ Designated as safety issue: No ]
- Pulmonary endurance as measured by a 2- and 6-minute walk test [ Designated as safety issue: No ]
- leukotriene levels in the urine and blood and leukotriene receptor expression on activated circulating immune cells [ Designated as safety issue: No ]
- Other chronic graft-vs-host disease manifestations [ Designated as safety issue: No ]
- Quality of life and function parameters [ Designated as safety issue: No ]
- Overall survival at 2 years [ Designated as safety issue: No ]
|Study Start Date:||March 2008|
|Estimated Study Completion Date:||May 2015|
|Estimated Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Drug: Montelukast sodium
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.
To evaluate if montelukast stabilizes or improves pulmonary function in patients with BO after BMT using FEV-1 changes as primary endpoints, and oxygen saturation, pulmonary function test (PFT) parameters (FEF 25-75, RV and RV/FVC, DLC02, FEV-1/FVC, FEV-1/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 cGVHD manifestations, quality of life, and overall survival.
Patients greater than or equal to 6 years old with bronchiolitis obliterans following stem cell transplantation for any disease indication may be enrolled.
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 3 institutions: NIH, Johns Hopkins Hospital, and Hackensack Hospital. Forty-five patients will be enrolled on this trial.
|Contact: Kirsten M Williams, M.D.||(301) firstname.lastname@example.org|
|Contact: Ronald E Gress, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|United States, Washington|
|Fred Hutchinson Cancer Research Center||Recruiting|
|Seattle, Washington, United States, 28104|
|Principal Investigator:||Ronald E Gress, M.D.||National Cancer Institute (NCI)|