Clinical trial NCT00200967: Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)
Official title: Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Asthma Clinical Research Network
First posted: 2005-09-20
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Morning (AM) Peak Expiratory Flow (PEF) Rate
timeFrame: 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 outcomes:
measure: Evening (PM) Peak Expiratory Flow (PEF) Rate
timeFrame: 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
measure: Peak Expiratory Flow (PEF) Variability
timeFrame: 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
measure: Asthma Symptoms
timeFrame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Rescue Medication (Ipratropium and Albuterol) Use
timeFrame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
timeFrame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
timeFrame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
timeFrame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Exhaled Nitric Oxide (eNO)
timeFrame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
measure: Exhaled Breath Condensate (EBC)
timeFrame: Clinic visits at weeks 0, 10, and 18 of each treatment period
measure: Methacholine Provocative Concentration 20 (PC20)
timeFrame: Clinic visits at weeks 0 and 18 of each treatment period
measure: Asthma Control Questionnaire (ACQ)
timeFrame: Clinic visits at weeks 0 and 18 of each treatment period
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Medical & Research Center
state: Colorado
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Madison
country: United States
facility: University of Wisconsin Madison
state: Wisconsin
Study officials:
affiliation: University of California, San Francisco
name: Homer Boushey
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Mario Castro
role: PRINCIPAL_INVESTIGATOR
affiliation: Milton S. Hershey Medical Center
name: Vernon M. Chinchilli, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital
name: Elliot Israel
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Robert Lemanske
role: PRINCIPAL_INVESTIGATOR
affiliation: National Jewish Medical & Research Center
name: Richard Martin
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Health Sciences
name: Stephen Peters
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Stephen Wasserman
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske RF Jr, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman SI, Israel E; National Heart, Lung and Blood Institute's Asthma Clinical Research Network. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet. 2009 Nov 21;374(9703):1754-64. doi: 10.1016/S0140-6736(09)61492-6.