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 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....
|Bronchiolitis Obliterans Chronic Graft Versus Host Disease Leukotriene Montelukast Stem Cell Transplant||Drug: Singular (Montelukast Sodium)||Phase 2|
|Study Design:||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|
- Number of Participants With Stable or Improved Predicted Forced Expiratory Volume 1 (FEV-1) With Published Literature [ Time Frame: 180 days ]Responsive disease (RD) will be defined as ≥15% absolute improvement in the percentage predicted FEV-1. Progressive disease (PD) will be defined as >15% decrease in FEV-1 documented on 2 pulmonary function test (PFT) evaluations greater than 2 weeks apart. Stable disease (SD) will be defined as <15% change in the absolute FEV-1.
- Number of Participants With Improved, Stable or Declined Forced Expiratory Volume 1 (FEV-1) Slope at 6 Months [ Time Frame: 180 days ]FEV-1 slope of decline was generated using regression line of FEV-1 value vs. days post hematopoietic stem cell transplant. Responsive disease (RD) for the slope of FEV-1 change will be an increase in the slope of absolute FEV-1. Progressive disease (PD) for the slope of FEV-1 change will be a decrease in the slope of absolute FEV-1. Stable disease (SD) for the slope of FEV-1 change will be a 0 change in FEV-1 slope.
- Number of Participants With Adverse Events [ Time Frame: 71 months and 17 days ]Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
- Timed Walk Test [ Time Frame: 2 minutes and 6 minutes ]A timed walk test was preformed to measure pulmonary endurance.
- Forced Expiratory Flow 25-75 (FEF25-75) in Pediatric and Adult Patients Greater Than 6 Years With Bronchiolitis Obliterans [ Time Frame: Baseline, 3 and 6 months on study, and 6 and 18 months post study drug ]Baseline impairment is <20% of predicted. Pulmonary function for children must be calculated using the NHANES criteria.
- Forced Expiratory Volume 1 (FEV-1)/Vital Capacity (VC) [ Time Frame: Baseline ]Pulmonary function test performed for eligibility and baseline.
- Residual Volume (RV) in Pediatric and Adult Patients Greater Than 6 Years With Bronchiolitis Obliterans [ Time Frame: Baseline, 3 month and 6 month on study, and 6 and 18 months post study drug. ]Residual volume ≥120% baseline value is evidence of obstruction. A decrease below 120% will signify response, any value >120% is non-responsive disease. Pulmonary function for children must be calculated using the NHANES criteria.
- Carbon Monoxide Diffusing Capacity (DLC02) in Adults Only With Bronchiolitis Obliterans [ Time Frame: Baseline, 3 month and 6 month on study, and 6 and 8 months post study drug ]Baseline impairment is defined as a decrease in DLC0 of at least 25%.
- Ratio of Forced Expiratory Volume 1 (FEV-1)/Forced Vital Capacity (FVC) [ Time Frame: Baseline and 6 cycle pulmonary function tests ]Baseline impairment is <20% of predicted
- Leukotriene Levels (LTB4 and Cysteinyl Leuotrienes (CysLT)) in the Urine Before and After Treatment [ Time Frame: After cycle 3 and cycle 6 ]A 24 hour urine will be collected to measure leukotriene levels after cycle 3 and cycle 6.
- Leukotriene Levels (LTB4 and Cysteinyl Leukotrienes (CysLT)) in the Blood Before and After Treatment [ Time Frame: Pretreatment and after cycle 3 and cycle 6 ]Blood will be collected and processed for multiparameter flow cytometry to measure leukotriene levels on circulating immune cells (cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8) + T cells, cluster of differentiation 19 (CD19) + B cells, cluster of differentiation 14 (CD14)+ monocytes, macrophages, neutrophils, and eosinophils).
- Leukotriene Receptor Expression (BLT or Cysteinyl Leukotrienes (CysLT)) on Activated Circulating Immune Cells Before and After Treatment [ Time Frame: Pretreatment and after cycle 3 and cycle 6 ]Leukotriene receptor expression on immune cells was analyzed by multiparameter flow cytometry and cytokine studies.
- Number of Participants With Chronic Graft Versus Host Disease (cGVHD) - Skin [ Time Frame: Baseline, 3 month and 6 months on study, and 6 and 18 months post study drug. ]cGVHD was defined by the National Institutes of Heath (NIH) Consensus staging.
- Percentage Overall 2-Year Survival [ Time Frame: 2 years ]Percentage of participants alive at 2 years.
- Quality of Life (QOL) Score at Baseline and Follow-up [ Time Frame: Pretreatment, after cycles 3 and 6, and 6 and 18 months post study drug ]QOL assessment was conducted using the VARNI for subjects age 5-18 years of age and by SF-36(V2) and FACIT-G, FACT-BMT for those >18 years of age
- Number of Non-Infected Participants at Baseline With Cysteinyl Leukotriene Receptor Expression on Cluster of Differentiation (CD4) and CD8 T Cells, Granulocytes, and Eosinophils in Bronchoalveolar Lavage (BAL) Fluid [ Time Frame: Day 1 of study ]Fluid from the bronchoalveolar lavage in adult participants (pediatric optional) will be collected and sent to the lab to be evaluated for infectious diseases by flow cytometry
- Residual Volume (RV/) Forced Vital Capacity (FVC) Measure (Adults Only) [ Time Frame: Baseline, after 6 cycles, and 6 and 18 months post study drug ]≥120% baseline value is evidence of obstruction. A decrease below 120% will signify response, any value >120% is non-responsive disease.
|Study Start Date:||March 2008|
|Estimated Study Completion Date:||May 2018|
|Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
Experimental: Montelukast to Treat Bronchiolitis Obliterans
Montelukast for the treatment of BO following allogeneic or autologous stem cell transplant.
Drug: Singular (Montelukast Sodium)
Singular (Montelukast Sodium):5-10 mg (weight based dosing) by mouth (PO) hour of sleep (HS)
Hide Detailed Description
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 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.
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 2 institutions: National Institutes of Health (NIH) and Fred Hutchinson Cancer Research Center. Forty-five patients will be enrolled on this trial.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00656058
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Ronald E Gress, M.D.||National Cancer Institute (NCI)|