Leukotriene Polymorphisms and Montelukast Response - Ancillary to LoDo Trial
Leukotriene Polymorphisms and Montelukast Response - Ancillary to LoDo Trial
To elucidate the mechanisms underlying inter-patient variation in response to montelukast, a
 drug for asthma.
BACKGROUND:

 Asthma is a common disease caused by a complex interaction between genetic and environmental
 factors. Asthma afflicts 17 million Americans. In 1999, more than 5000 persons died from
 asthma. Given the significant mortality and morbidity associated with asthma, it is important
 to continue to develop new strategies for intervention. Leukotriene antagonists are thought
 to be the most innovative approach to asthma therapy in 20 years. Despite their demonstrated
 efficacy, safety and popularity, the leukotriene antagonists are associated with a
 significant degree of inter-patient variability in response, which can limit their safety,
 efficacy and cost-effectiveness. Several polymorphisms in leukotriene pathway genes can
 contribute to variability in response. The project will determine if polymorphisms in genes
 encoding 5-lipoxygenase, leukotriene A4hydrolase, LTC4 synthase, multi-drug resistance
 protein 1 (MRP1) and LT1 receptor proteins are determinants of response to montelukast
 treatment.

 The study is in response to an Request for Applications entitled Ancillary Studies in Heart,
 Lung, and Blood Disease Trials which was released by the NHLBI in June 2000 to conduct
 mechanistic studies in clinical trials related to heart, lung and blood diseases.
 Specifically, this initiative focuses on the utilization of patients and patient materials
 from such trials to study the mechanisms underlying the interventions, the mechanisms of
 disease pathogenesis, surrogate markers or biomarkers of disease activity and therapeutic
 effect and the mechanisms of human cardiopulmonary and hematologic function. Studies aimed at
 accelerating the development of new technologies within the context of the mechanistic
 investigations are also encouraged.

 DESIGN NARRATIVE:

 DNA will be collected from patients participating in a parent clinical trial entitled:
 Effectiveness of Low Dose Theophylline as Add-On Therapy in the Treatment of Asthma (LoDo
 Trial). 627 patients from 19 Asthma Clinical Research Centers will be randomly assigned to
 receive placebo, or low dose theophylline (300 mg/day) or montelukast, 10 mg daily, for 6
 months. Stepwise Linear and Poisson regressions will be performed on outcomes including
 treatment and genetic covariates, and interaction terms between treatment arm and genetic
 makeup. Polymorphisms that are highly associated with response can lead to the development of
 genetic tests that will identify patients most likely to benefit from montelukast treatment.
 This information may lead to individualization of asthma medications based on the genetic
 make-up of the patient.
No eligibility criteria