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

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.

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