Pharmacogenetics of b2-Agonists in Asthma.

This study will help to find out if having a certain genetic makeup influences how a person with asthma responds to salmeterol, one of the two drugs in Advair(R).

Study Overview

• Status: Completed
• Conditions: Asthma

Detailed Description

Patients are being asked to take part in this research study because they have asthma. This clinical research study is being done to see if an asthmatic's gene make-up (DNA is made up of genes) affects the way they respond to a particular asthma medication called salmeterol. Certain genes make people tall or short. Certain genes give people brown or black hair. Similarly, certain genes may be associated with the way patients respond to asthma medications.

Salmeterol xinafoate (a long acting bronchodilator) and fluticasone propionate (an inhaled corticosteroid) are the medicines contained in Advair Diskus. During this study, patients with asthma will receive fluticasone inhaler (called Flovent) and Advair Diskus. The investigators want to find out if patients with asthma with certain genes respond in different ways to the salmeterol in Advair Diskus. The investigators also want to find out if patients with asthma with certain genes who are treated with salmeterol for two weeks have their airways open up less than usual when they use albuterol.

• Study Type: Observational
• Enrollment (Actual): 88

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study population was Whites and African Americans with specific ADRB2 diplotypes aged 10 years or older with physician diagnosed asthma according to American Thoracic Society criteria for at least 3 months, forced expiratory volume in the first second (FEV1) >= 60% of predicted normal values for age, height, and gender, and a methacholine challenge test provocative concentration (20% fall in FEV1) of <=12]mg/ml.

Description

Inclusion Criteria:

• Diplotype: Whites with specific diplotype and African Americans with specific diplotypes.
• Gender: Male or female. Women are eligible if they are not pregnant or lactating. Females subjects of childbearing potential will undergo a urine pregnancy test prior to each methacholine challenge test.
• Age: 10 years and older.
• Asthma Diagnosis: Physician diagnosed asthma according to American Thoracic Society criteria for at least 3 months.
• Asthma Therapy: There is no requirement for previous asthma therapy to be included in this study.
• Asthma Severity: forced expiratory volume in the first second (FEV1) must be >= 60% of predicted normal values for age, height, and gender.
• methacholine challenge test provocative concentration (20% fall in FEV1) of <=12]mg/ml.

Exclusion Criteria:

• History of life-threatening asthma: Any episode of asthma requiring intubation associated with hypercapnia, respiratory arrest, or hypoxic seizures.
• Asthma instability: Hospitalization for asthma within 3 months of Visit 1.
• Concurrent respiratory disease: Any respiratory disease other than asthma.
• Sensitivities: Sensitivities to methacholine, Flovent® MDI, ipratropium bromide, albuterol, or Advair Diskus® that would put the safety of the subject at risk.
• Respiratory Tract Infection: Any sinus, middle ear, oropharyngeal, upper or lower respiratory tract infection that has not resolved at least 2 weeks immediately preceding Visit 1, or for which antibiotic therapy has not been completed at least 2 weeks prior to Visit 1.
• Expected exposure to pollen allergen to which the patient is sensitive (by medical history of symptoms) during the 29 day study period. These patients can be studied when pollen exposure to which they are sensitive will not occur.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Crossover
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Whites ADRB2:ARG16ARG; All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol for 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
Whites ADRB2:GLY16GLY; All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol for 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
African American ADRB2:ARG16ARG; All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol for 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
African American ADRB2:GLY16GLY; All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol for 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log10 PC20 to Methacholine After Visit 2	Visit 2 log10 PC20 after receiving 2 weeks of Flovent	Visit 2:12 hours after last dose of Flovent
Log10 PC20 to Methacholine After Visit 3	Visit 3 Log10 PC20 after receiving 2 weeks of Advair	Visit 3:12 hours after the last dose of Advair
Log10 PC20 to Methacholine After Visit 4	Visit 4 log10 PC20 to Methacholine after stopping Advair	36 hours after the last dose of Advair

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bronchodilator Response to Methacholine (PC20) After Visit 2	The area under the curve (AUC) bronchodilator response after Visit 2 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Flovent for 2 weeks at Visit 2.	0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Flovent.
Bronchodilator Response Following Methacholine Challenge at Visit 3	The area under the curve (AUC) bronchodilator response after Visit 3 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Advair for 2 weeks at Visit 3.	0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Advair
Bronchodilator Response Following Methacholine Challenge at Visit 4	The area under the curve (AUC) bronchodilator response after Visit 4 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had discontinued Advair for 36 hours.	0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 36 hours after the last dose of Advair

Collaborators and Investigators

• Sponsor: Nemours Children's Clinic
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Florida
• Investigators: Principal Investigator: Kathryn Blake, Pharm.D., Nemours Children's Clinic

Publications and helpful links

General Publications

• Blake K, Cury JD, Hossain J, Tantisira K, Wang J, Mougey E, Lima J. Methacholine PC20 in African Americans and whites with asthma with homozygous genotypes at ADRB2 codon 16. Pulm Pharmacol Ther. 2013 Jun;26(3):342-7. doi: 10.1016/j.pupt.2013.01.009. Epub 2013 Feb 4.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: June 27, 2008
• First Submitted That Met QC Criteria: July 1, 2008
• First Posted (Estimate): July 2, 2008

Study Record Updates

• Last Update Posted (Actual): February 22, 2018
• Last Update Submitted That Met QC Criteria: February 20, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Asthma; African American; Pharmacogenetics; Salmeterol; White
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: 82211; K23HL081245 (U.S. NIH Grant/Contract)