Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)

Study Overview
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Brief Summary
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The purpose of this trial is to determine whether regularly scheduled use of an inhaled long-acting beta agonist (salmeterol) in the setting of concomitant use of inhaled corticosteroids (beclomethasone hydroflouroalkane (HFA) inhaler) will have a detrimental effect on asthma control in people who bear the B16-Arg/Arg genotype of the beta-2 adrenergic receptor gene, as compared to people with asthma of similar severity who bear the B16-Gly/Gly genotype.

Detailed Description
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BACKGROUND: The purpose of this study is to compare the effects of a long-acting beta agonist in patients with asthma receiving inhaled corticosteroids who express two distinct polymorphisms of the beta-2 adrenergic receptor. DESIGN NARRATIVE: Participants were homozygous for arginine or glycine at the 16th amino-acid position of the β-2 adrenergic receptor (B16 Arg/Arg or B16 Gly/Gly). Individuals were matched against their opposite genotype by forced expiratory volume in one second (FEV1) and race. Matched participants entered an 8-week run-in period. This is a 62-week crossover design where subjects receive the following therapies: Beclomethasone HFA (240 µg twice a day (BID)) + as-needed (PRN) albuterol: 8-week run-in Beclomethasone HFA (240 µg BID) + salmeterol (50 µg BID) + PRN ipratropium bromide + PRN albuterol: 18-week treatment period Beclomethasone HFA (240 µg BID) + PRN albuterol: 8-week run-out Beclomethasone HFA (240 µg BID) + placebo salmeterol + PRN ipratropium bromide + PRN albuterol: 18-week treatment period Beclomethasone HFA (240 µg BID) + PRN albuterol: 10-week run-out The order of treatments received during the two treatment periods is randomized.

Official Title
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Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)

Conditions
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Asthma

Intervention / Treatment
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* Drug: salmeterol
* Drug: beclomethasone HFA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, ages 18 and older Clinical history consistent with asthma For subjects regularly using inhaled corticosteroids, FEV1 50% of predicted, methacholine PC20 FEV1 16 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol For subjects not regularly using inhaled corticosteroids, FEV1 40% of predicted, methacholine PC20 FEV1 8 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol Genotype eligibility (determined during screening) Exclusion Criteria: Smoker (total smoking history must be less than 10 pack years) Significant unstable medical condition other than asthma History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the past 10 years Pregnant or lactating

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B16 Arg/Arg<br>B16 Arg/Arg genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone hydroflouroalkane (HFA), followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA | Drug: salmeterol<br>* 50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)<br>* Other names: Serevent;Drug: beclomethasone HFA<br>* 240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)<br>* Other names: QVAR;|
| Experimental: B16 Gly/Gly<br>B16 Gly/Gly genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone HFA, followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA | Drug: salmeterol<br>* 50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)<br>* Other names: Serevent;Drug: beclomethasone HFA<br>* 240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)<br>* Other names: QVAR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morning (AM) Peak Expiratory Flow (PEF) Rate | Change between placebo salmeterol and active salmeterol for AM PEF rate | Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evening (PM) Peak Expiratory Flow (PEF) Rate | Change between placebo salmeterol and active salmeterol for PM PEF rate | Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Peak Expiratory Flow (PEF) Variability | Change between placebo salmeterol and active salmeterol for PEF variability, where PEF variability is defined as 100% x (PM PEF - AM PEF)/(PM PEF) | Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Asthma Symptoms | Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe). | Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Rescue Medication (Ipratropium and Albuterol) Use | Change between placebo salmeterol and active salmeterol for rescue medication use | Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator | Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator | Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator | Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Exhaled Nitric Oxide (eNO) | Change between placebo salmeterol and active salmeterol for eNO | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | 
| Exhaled Breath Condensate (EBC) | Change between placebo salmeterol and active salmeterol for EBC | Clinic visits at weeks 0, 10, and 18 of each treatment period | 
| Methacholine Provocative Concentration 20 (PC20) | Change between placebo salmeterol and active salmeterol for methacholine PC20 | Clinic visits at weeks 0 and 18 of each treatment period | 
| Asthma Control Questionnaire (ACQ) | Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control). | Clinic visits at weeks 0 and 18 of each treatment period |