Trial | NCT00200967  Report issue

Official Title

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

  • Phase

    Phase 3

  • Study Type

    Interventional

  • Study Participants

    87
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.
Study Started
Dec 31
2004
Primary Completion
Feb 29
2008
Study Completion
Feb 29
2008
Results Posted
Jun 02
2009
Estimate
Last Update
Jan 23
2018

Drug salmeterol

50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)

  • Other names: Serevent

Drug beclomethasone HFA

240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)

  • Other names: QVAR

B16 Arg/Arg Experimental

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

B16 Gly/Gly Experimental

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

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

Summary

B16 Arg/Arg

B16 Gly/Gly

All Events

Event Type Organ System Event Term B16 Arg/Arg B16 Gly/Gly

Morning (AM) Peak Expiratory Flow (PEF) Rate

Change between placebo salmeterol and active salmeterol for AM PEF rate

B16 Arg/Arg

-21.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -31.0 to -12.0

B16 Gly/Gly

-22.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -32.0 to -11.0

Evening (PM) Peak Expiratory Flow (PEF) Rate

Change between placebo salmeterol and active salmeterol for PM PEF rate

B16 Arg/Arg

-25.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -34.0 to -16.0

B16 Gly/Gly

-24.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -34.0 to -14.0

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)

B16 Arg/Arg

0.2
percentage (Least Squares Mean)
95% Confidence Interval: -0.6 to 1.0

B16 Gly/Gly

0.7
percentage (Least Squares Mean)
95% Confidence Interval: 0.0 to 1.4

Asthma Symptoms

Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).

B16 Arg/Arg

0.04
units on a scale (Mean)
95% Confidence Interval: 0.0 to 0.12

B16 Gly/Gly

Rescue Medication (Ipratropium and Albuterol) Use

Change between placebo salmeterol and active salmeterol for rescue medication use

B16 Arg/Arg

0.2
puffs per day (Mean)
95% Confidence Interval: 0.0 to 0.5

B16 Gly/Gly

Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator

Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator

B16 Arg/Arg

-0.08
liters (Least Squares Mean)
95% Confidence Interval: -0.13 to -0.03

B16 Gly/Gly

-0.04
liters (Least Squares Mean)
95% Confidence Interval: -0.09 to 0.0

Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator

Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator

B16 Arg/Arg

-0.04
liters (Least Squares Mean)
95% Confidence Interval: -0.08 to 0.01

B16 Gly/Gly

-0.03
liters (Least Squares Mean)
95% Confidence Interval: -0.09 to 0.03

Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator

Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator

B16 Arg/Arg

-17.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -27.0 to -8.0

B16 Gly/Gly

-17.0
liters per minute (Least Squares Mean)
95% Confidence Interval: -27.0 to -6.0

Exhaled Nitric Oxide (eNO)

Change between placebo salmeterol and active salmeterol for eNO

B16 Arg/Arg

0.12
parts per billion (Geometric Mean)
95% Confidence Interval: -0.01 to 0.24

B16 Gly/Gly

-0.02
parts per billion (Geometric Mean)
95% Confidence Interval: -0.15 to 0.11

Exhaled Breath Condensate (EBC)

Change between placebo salmeterol and active salmeterol for EBC

B16 Arg/Arg

-0.1
pH (Least Squares Mean)
95% Confidence Interval: -0.45 to 0.26

B16 Gly/Gly

-0.03
pH (Least Squares Mean)
95% Confidence Interval: -0.37 to 0.31

Methacholine Provocative Concentration 20 (PC20)

Change between placebo salmeterol and active salmeterol for methacholine PC20

B16 Arg/Arg

0.06
milligrams per milliliter (Geometric Mean)
95% Confidence Interval: -0.6 to 0.71

B16 Gly/Gly

-1.27
milligrams per milliliter (Geometric Mean)
95% Confidence Interval: -1.87 to -0.66

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).

B16 Arg/Arg

0.13
units on a scale (Least Squares Mean)
95% Confidence Interval: -0.06 to 0.32

B16 Gly/Gly

0.11
units on a scale (Least Squares Mean)
95% Confidence Interval: -0.04 to 0.26

Total

87
Participants

Age, Continuous

41
years (Mean)
Standard Deviation: 12

Age, Categorical

Region of Enrollment

Sex: Female, Male

First Treatment Period

B16 Arg/Arg

B16 Gly/Gly

Wash-out Period

B16 Arg/Arg

B16 Gly/Gly

Second Treatment Period

B16 Arg/Arg

B16 Gly/Gly

Run-out Period

B16 Arg/Arg

B16 Gly/Gly

Drop/Withdrawal Reasons

B16 Arg/Arg

B16 Gly/Gly