Predicting the Response to Montelukast by Genetic Variation in Asthmatics

Asthma Clinical Trial

Official title:

Predicting the Bronchoprotective Response to a Leukotriene Modifier by Genetic Polymorphism

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00116324
• Other study ID #: 2002-P-001696
• Status: Completed
• Phase: Phase 3
• Start date: April 2003
• Est. completion date: December 2006

Study information

• Verified date: May 2021
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to examine a specific variation in the genetic code for an enzyme (LTC4 synthase) which plays an important role in the airway inflammation associated with asthma. We hypothesize that asthmatic patients with this variant gene will have a better response to montelukast than patients with the wild type gene, as measured by the ability of montelukast to protect against a hypertonic saline challenge.

Description:

Multiple genetic polymorphisms in the leukotriene pathway have been described but their clinical relevance is unclear. A single nucleotide polymorphism in the LTC4 synthase promoter region has been associated with increased LTC4 synthase mRNA and a trend toward improved bronchodilatory response to leukotriene modifiers in severe asthmatics. This study will examine mild to moderate asthmatics with the variant gene and evaluate the bronchoprotective response of montelukast in a double-blind, placebo-controlled cross-over fashion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: December 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male and female subjects, age 18-55

• Clinical history consistent with asthma

• Mild to moderate asthma as determined by pulmonary function tests--60% or higher of predicted FEV1 for age, sex and race.

• Response to hypertonic saline, which will be the main outcome variable measured.

Exclusion Criteria:

• Smokers (total lifetime smoking history>10 pack-years, any in the past year)

• Pregnant woman-if of childbearing age, not using an acceptable form of birth control.

• Use of a leukotriene modifier within the past month

• Use of inhaled or oral steroids within the past month.

• Emergency room visit for asthma exacerbation within the past 6 weeks.

• Intubation for asthma exacerbation in the past 10 years.

• Adverse reaction to inhaled beta-agonists in the past.

• No recent (past 48 hours) use of anticholinergics, theophylline, antihistamines, pseudoephedrine.

• Patients will also be asked not to use any short acting beta-agonists for 6 hours and long-acting beta-agonists for 48 hours before their initial visit (when pulmonary function evaluation will be performed).

• Lung disease other than asthma

• Significant medical illness other than asthma

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Montelukast

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

References & Publications (7)

Anderson PJ, Garshick E, Blanchard JD, Feldman HA, Brain JD. Intersubject variability in particle deposition does not explain variability in responsiveness to methacholine. Am Rev Respir Dis. 1991 Sep;144(3 Pt 1):649-54. — View Citation

Drazen JM, O'Brien J, Sparrow D, Weiss ST, Martins MA, Israel E, Fanta CH. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis. 1992 Jul;146(1):104-8. — View Citation

Drazen JM, Yandava CN, Dubé L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet. 1999 Jun;22(2):168-70. — View Citation

In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP, Serino K, Kim SW, De Sanctis GT, Yandava C, Pillari A, Rubin P, Kemp J, Israel E, Busse W, Ledford D, Murray JJ, Segal A, Tinkleman D, Drazen JM. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest. 1997 Mar 1;99(5):1130-7. — View Citation

Sampson AP, Siddiqui S, Buchanan D, Howarth PH, Holgate ST, Holloway JW, Sayers I. Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax. 2000 Oct;55 Suppl 2:S28-31. — View Citation

Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet. 1997 Nov 29;350(9091):1599-600. — View Citation

Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW, Dollery CT. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989 Mar 18;1(8638):584-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in hypertonic saline PD20
Secondary	Improved asthma control
Secondary	Change in exhaled breath condensate inflammatory markers