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

• Evening (PM) Peak Expiratory Flow (PEF) Rate [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
  Change between placebo salmeterol and active salmeterol for PM PEF rate
• Peak Expiratory Flow (PEF) Variability [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
  Change between placebo salmeterol and active salmeterol for PEF variability, where PEF variability is defined as 100% x (PM PEF - AM PEF)/(PM PEF)
• Asthma Symptoms [ Time Frame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: Yes ]
  Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).
• Rescue Medication (Ipratropium and Albuterol) Use [ Time Frame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: Yes ]
  Change between placebo salmeterol and active salmeterol for rescue medication use
• Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator [ Time Frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator
• Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator [ Time Frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator
• Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator [ Time Frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator
• Exhaled Nitric Oxide (eNO) [ Time Frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for eNO
• Exhaled Breath Condensate (EBC) [ Time Frame: Clinic visits at weeks 0, 10, and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for EBC
• Methacholine Provocative Concentration 20 (PC20) [ Time Frame: Clinic visits at weeks 0 and 18 of each treatment period ] [ Designated as safety issue: No ]
  Change between placebo salmeterol and active salmeterol for methacholine PC20
• Asthma Control Questionnaire (ACQ) [ Time Frame: Clinic visits at weeks 0 and 18 of each treatment period ] [ Designated as safety issue: Yes ]
  Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control).

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.

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.

• Drug: salmeterol
  50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)
  Other Name: Serevent
• Drug: beclomethasone HFA
  240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)
  Other Name: QVAR

• Experimental: B16 Arg/Arg
  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
  Interventions:

  • Drug: salmeterol
  • Drug: beclomethasone HFA
• Experimental: B16 Gly/Gly
  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
  Interventions:

  • Drug: salmeterol
  • Drug: beclomethasone HFA

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

• National Heart, Lung, and Blood Institute (NHLBI)
• Asthma Clinical Research Network