How Different Beta-2 Receptor Genotypes Affect an Asthmatic's Response to Regular Salmeterol Treatment - Full Text View

Sponsor:	Brigham and Women's Hospital
Information provided by:	Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT00595361

Purpose

The purpose of the study is to find out how well a long-acting beta agonist like salmeterol works in people with different forms of the same gene. Our hypothesis is that asthmatics with the Arg/Arg genotype will have loss of bronchoprotection against exercise-induced asthma with regular salmeterol treatment, as compared to asthmatics with the Gly/Gly genotype.

Condition	Intervention
Asthma	Drug: salmeterol

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	The Effect of Beta-2 Adrenergic Polymorphisms on the Bronchoprotective Effects of Regular Salmeterol Treatment in Asthma

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Asthma Exercise and Physical Fitness

Drug Information available for: Salmeterol Salmeterol xinafoate

U.S. FDA Resources

Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:

comparison of the maximum percent fall in FEV1 after exercise challenge at the end of the 2-week treatment period between Arg/Arg and Gly/Gly patients [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

comparison of the maximum percent fall in FEV1 from pre-salmeterol baseline to the end of the 2-week treatment period between Arg/Arg and Gly/Gly subjects [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
comparison of the maximum percent fall in FEV1 after 1st dose of salmeterol to the end of the 2-week treatment period between Arg/Arg and Gly/Gly subjects [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	30
Study Start Date:	January 2008
Estimated Study Completion Date:	March 2012
Estimated Primary Completion Date:	September 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Arg/Arg Arg/Arg subjects on 2 week salmeterol treatment	Drug: salmeterol salmeterol 50 micrograms twice daily for 2 weeks
Active Comparator: Gly/Gly Gly/Gly subjects on 2 week salmeterol treatment	Drug: salmeterol salmeterol 50 micrograms twice daily for 2 weeks

Detailed Description:

In many patients with asthma, exercise-induced bronchoconstriction is a common and oftentimes limiting characteristic. Inhaled β2-adrenoreceptor agonists like albuterol are the most effective treatments available for the relief of acute asthma symptoms. However, there is evidence that regular use may lead to adverse effects in some patients. Previous studies have shown that polymorphisms of the β2-adrenergic receptor can influence airway responses to regular inhaled beta-agonist treatment.

Pharmacogenetics is the study of how genetic differences influence the variability in patients' responses to therapy, both therapeutic and adverse. Genetic susceptibility and environmental factors both play major roles in the etiology of asthma. The strong familial clustering of asthma has lead to a surge of research into the genetic predisposition of asthma. The aim of the present study is to utilize a double-blinded prospective cohort study to investigate whether genotype-specific effects occur when assessing the duration of protection conferred against exercise-induced bronchoconstriction by regular salmeterol treatment.

Eligibility

Ages Eligible for Study:	18 Years to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Both male and female
18 to 50 years of age
Resting FEV1 ≥ 65% of predicted normal
Exercise-induced bronchoconstriction defined as a decrease in FEV1 of ≥ 20% following a standardized exercise challenge when compared to pre-exercise baseline FEV1 value measured 5 minutes before exercise
Must be Arg/Arg or Gly/Gly genotype

Exclusion Criteria:

Long-acting beta agonist use within 12 weeks of the first exercise challenge
Smoking within past 12 months
Greater than 10-pack years smoking history
Unresolved signs and/or symptoms of an upper respiratory tract infection within 4 weeks of first exercise challenge
Asthma exacerbation within 4 weeks of first exercise challenge requiring change in type, dose or frequency of medications and/or an unscheduled visit to an health care provider, including emergency room or hospital
Subject has exercised or performed strenuous activity within 72 hours of the first exercise challenge
Subject has been exposed to cold air sufficient to provoke symptoms of bronchospasm within 2 hours of exercise challenge
In addition to asthma, the subject has an active, acute or chronic pulmonary disorder documented by history, physical examination, or chest x-ray
Subject has evidence of ischemic, valvular, hypertrophic, familial or other forms of heart disease that would put the subject at risk during exercise testing or that would interfere with the ability to achieve protocol-specified heart rates during exercise testing
Subject has used systemic corticosteroids within 1 month of first exercise challenge

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00595361

Locations

United States, Massachusetts
Asthma Research Center, Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

Principal Investigator:

Elliot Israel, M.D.

Asthma Research Center, Brigham and Women's Hospital

More Information

Publications:

Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, Cooper DM, Fahy JV, Fish JE, Ford JG, Kraft M, Kunselman S, Lazarus SC, Lemanske RF, Martin RJ, McLean DE, Peters SP, Silverman EK, Sorkness CA, Szefler SJ, Weiss ST, Yandava CN. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med. 2000 Jul;162(1):75-80.

Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, Kraft M, Kunselman SJ, Lazarus SC, Lemanske RF Jr, Liggett SB, Martin RJ, Mitra N, Peters SP, Silverman E, Sorkness CA, Szefler SJ, Wechsler ME, Weiss ST, Drazen JM; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet. 2004 Oct 23;364(9444):1505-12.

Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med. 2006 Mar 1;173(5):519-26. Epub 2005 Dec 1.

Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med. 1994 May;88(5):363-8.

Yates DH, Worsdell M, Barnes PJ. Effect of regular salmeterol treatment on albuterol-induced bronchoprotection in mild asthma. Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):988-91.

Nelson JA, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden ER Jr. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med. 1998 Jul 16;339(3):141-6.

Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax. 2006 Nov;61(11):940-4. Epub 2006 Jun 13.

Israel E. Genetics and the variability of treatment response in asthma. J Allergy Clin Immunol. 2005 Apr;115(4 Suppl):S532-8. Review.

Responsible Party:	Elliot Israel, M.D., Asthma Research Center/Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT00595361 History of Changes
Other Study ID Numbers:	2007-P-002199
Study First Received:	January 7, 2008
Last Updated:	July 11, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Brigham and Women's Hospital:

asthma
exercise induced asthma
exercise induced bronchoconstriction
long acting beta agonist
salmeterol

exercise challenge
bronchoprotection
beta 2 adrenergic receptor polymorphisms
pharmacogenetics

Additional relevant MeSH terms:

Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Adrenergic Agents
Salmeterol
Neurotransmitter Agents

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 12, 2012