Evaluating Long Acting Beta Agonists Used to Treat Asthma Among Those With Either Arg/Arg or Gly/Gly Genotypes

Study Overview
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Brief Summary
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The investigators are conducting a study of asthma patients who use fluticasone with salmeterol (Advair) or any other combination of an inhaled corticosteroid (ICS) and a long acting beta agonist (LABA) to manage their asthma symptoms. Participants begin the study by continuing to use fluticasone with salmeterol or substituting fluticasone with salmeterol for their current ICS/LABA medication at their regular dose or the comparable dose(all study medications are provided) for a six-week period. Patients are then separated into 2 groups: one group is asked to use fluticasone (Flovent), the other to use fluticasone with salmeterol , twice daily over a 16-week period (patients will need to be seen monthly during this time). Neither study personnel nor patients will know which drug is being used. Patients are also asked to use a peak flow meter and record their daily results on a form, along with the number of puffs they use of their rescue inhaler each day. They also record any changes in asthma medications and information on any asthma episodes. The investigators hypothesize that there are certain patients with asthma who will do better when a long acting beta agonist is removed from their maintenance asthma medications.

Detailed Description
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Beta 2 (b2) agonists are the most common type of bronchodilator used to treat asthma. Beta 2 (b2) agonists are agents that bind to b2 receptors and cause muscle relaxation of the airways. There are different variants of the gene (genotypes) that influence how b2 agonists perform among the population. A recent study demonstrated that patients with mild asthma and the Arg/Arg variant at the 16th amino acid position have improved lung function and asthma control when albuterol (Proventil-HFA), a short acting b2 agonist, is replaced with a different class of bronchodilator. The investigators plan to study asthma patients with distinct genetic makeups of the b2 receptor; specifically Arg/Arg and Gly/Gly. Throughout the treatment period, patients will be instructed to use ipratropium bromide (Atrovent-HFA), a bronchodilator which works through a different mechanism for rescue therapy; albuterol will be available for use if necessary. The goal of this study is to determine if the withdrawal of a beta 2 agonist leads to improved asthma control in those asthmatic patients with the Arg/Arg genotype compared with those with the Gly/Gly genotype.

Official Title
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Arg/Arg Genotype and Long Acting Beta Agonists in Asthma. Improved Quality of Care for Patients With Asthma.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone with salmeterol
* Drug: Fluticasone HFA
* Drug: Ipratropium HFA
* Drug: Albuterol HFA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older History of moderate or severe and persistent asthma Currently being treated with a long acting beta agonist and inhaled corticosteroid Forced expiratory volume at one second (FEV1) > or = 70% at randomization visit (pulmonary function test result) Women of childbearing potential must be on an effective form of contraception Ability to read and understand English Exclusion Criteria: Active smoking or greater than 10-pack-year history of smoking History of intubation for asthma within the past 10 years Patients who are pregnant, become pregnant during the study or are breast feeding Major comorbidity including: severe cardiac disease, uncontrolled hypertension, poorly controlled diabetes, malignancy within the past 5 years (except non-melanoma skin lesions), and pulmonary disease other than asthma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arg/Arg genotype on Advair (Fluticasone with Salmeterol) HFA<br>Asthma patients with the Arg/Arg genotype who are randomized to continue the combination therapy of a specific long-acting beta 2 agonist (salmeterol) and inhaled corticosteroid (fluticasone) in the form of Advair HFA. | Drug: Fluticasone with salmeterol<br>* Fluticasone 45mcg, 115mcg, or 230mcg with salmeterol 21mcg, via HFA device, 2 puffs every 12 hrs, over 16 week study period.<br>* Other names: Advair HFA;Drug: Ipratropium HFA<br>* Primary as-needed rescue medication in all treatment groups<br>* Other names: Atrovent;Drug: Albuterol HFA<br>* Secondary as-needed rescue medication in all treatment groups<br>|
| Active Comparator: Gly/Gly genotype on Advair (Fluticasone with Salmeterol) HFA<br>Asthma patients with the Gly/Gly genotype who are randomized to continue the combination therapy of a specific long-acting beta 2 agonist (salmeterol) and inhaled corticosteroid (fluticasone) in the form of Advair HFA. | Drug: Fluticasone with salmeterol<br>* Fluticasone 45mcg, 115mcg, or 230mcg with salmeterol 21mcg, via HFA device, 2 puffs every 12 hrs, over 16 week study period.<br>* Other names: Advair HFA;Drug: Ipratropium HFA<br>* Primary as-needed rescue medication in all treatment groups<br>* Other names: Atrovent;Drug: Albuterol HFA<br>* Secondary as-needed rescue medication in all treatment groups<br>|
| Experimental: Arg/Arg genotype on Fluticasone HFA<br>Asthma patients with the Arg/Arg genotype who are randomized to fluticasone (Flovent HFA) alone. | Drug: Fluticasone HFA<br>* Fluticasone HFA alone at 44mcg, 110mcg or 220 mcg 2 puffs every 12 hrs, over 16 week study period.<br>* Other names: Flovent HFA;Drug: Ipratropium HFA<br>* Primary as-needed rescue medication in all treatment groups<br>* Other names: Atrovent;Drug: Albuterol HFA<br>* Secondary as-needed rescue medication in all treatment groups<br>|
| Experimental: Gly/Gly genotype on Fluticasone HFA<br>Asthma patients with the Gly/Gly genotype who are randomized to fluticasone (Flovent HFA) alone. | Drug: Fluticasone HFA<br>* Fluticasone HFA alone at 44mcg, 110mcg or 220 mcg 2 puffs every 12 hrs, over 16 week study period.<br>* Other names: Flovent HFA;Drug: Ipratropium HFA<br>* Primary as-needed rescue medication in all treatment groups<br>* Other names: Atrovent;Drug: Albuterol HFA<br>* Secondary as-needed rescue medication in all treatment groups<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Morning Peak Flow | Absolute change in morning peak flow at the end of the 16-week study period compared with baseline (last two weeks of run-in). Peak flow measurement is a test to measure air flowing out of the lung. | Up to 16 weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Forced Expiratory Volume in 1 Second (FEV1) Pre-Bronchodilator | Change in Forced Expiratory Volume in 1 Second (FEV1) Pre-Bronchodilator as measured by spirometry | Up to 16 weeks from baseline | 
| Change in Forced Expiratory Volume in 1 Second (FEV1) Post-Bronchodilator | Change in Forced Expiratory Volume in 1 Second (FEV1) Post-Bronchodilator as measured by spirometry | Up to 16 weeks from baseline | 
| Change in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted Pre-Bronchodilator | Change in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted Pre-Bronchodilator as measured by spirometry | Up to 16 weeks from baseline | 
| Change in Asthma Symptom Score | Asthma symptom score measures asthma symptoms on a scale from 0 to 3. 0 = No asthma symptoms; 1 = 1-3 asthma episodes each lasting 2 hours or less, all mild; 2= 4 or more asthma episodes that interfered with activity, play, school, or sleep for less than 2 hours; 3= 1 or more asthma episodes lasting longer than 2 hours, or resulting in shortening normal activity, or seeing a doctor, or going to a hospital. A higher score indicates a worse outcome. | Up to 16 weeks from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, beta agonist, bronchodilator, pulmonary, genotype, pharmacogenomics, corticosteroid, allergy, immunology