Asthma
Conditions
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.
Interventions
DRUGsalmeterol
50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)
DRUGbeclomethasone HFA
240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Asthma Clinical Research Network
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Morning (AM) Peak Expiratory Flow (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 | Change between placebo salmeterol and active salmeterol for AM PEF rate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Expiratory Flow (PEF) Variability | 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 | 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 | Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe). |
| Rescue Medication (Ipratropium and Albuterol) Use | Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for rescue medication use |
| Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator |
| Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator |
| Evening (PM) Peak Expiratory Flow (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 | Change between placebo salmeterol and active salmeterol for PM PEF rate |
| Exhaled Nitric Oxide (eNO) | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for eNO |
| Exhaled Breath Condensate (EBC) | Clinic visits at weeks 0, 10, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for EBC |
| Methacholine Provocative Concentration 20 (PC20) | Clinic visits at weeks 0 and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for methacholine PC20 |
| Asthma Control Questionnaire (ACQ) | Clinic visits at weeks 0 and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control). |
| Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator | Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period | Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator |
Countries
United States
Participant flow
Recruitment details
Recruitment for the LARGE trial began in November 2004 and the final participant visits occurred in February 2008. Seven academic medical centers throughout the US recruited the participants.
Pre-assignment details
474 participants were screened: 78 had B16 Arg/Arg genotype; 166 had B16 Gly/Gly genotype; 230 had Arg/Gly genotype. 47 matched Arg/Arg-Gly/Gly pairs entered the 8-week run-in period. 42 Arg/Arg were randomized (2 withdrew, 2 noncompliant, 1 lost); 45 Gly/Gly were randomized (1 withdrew, 1 noncompliant).
Participants by arm
| Arm | Count |
|---|---|
| B16 Arg/Arg B16 Arg/Arg 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 | 42 |
| B16 Gly/Gly B16 Arg/Arg 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 | 45 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Treatment Period | Pregnancy | 1 | 0 |
| First Treatment Period | Withdrawal by Subject | 5 | 1 |
| Run-out Period | Lost to Follow-up | 1 | 0 |
| Second Treatment Period | Withdrawal by Subject | 1 | 2 |
| Wash-out Period | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | B16 Gly/Gly | B16 Arg/Arg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 42 Participants | 87 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 12 | 39 years STANDARD_DEVIATION 11 | 41 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 45 participants | 42 participants | 87.0 participants |
| Sex: Female, Male Female | 29 Participants | 32 Participants | 61 Participants |
| Sex: Female, Male Male | 16 Participants | 10 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 42 | 20 / 45 |
| serious Total, serious adverse events | 1 / 42 | 4 / 45 |
Outcome results
Primary
Morning (AM) Peak Expiratory Flow (PEF) Rate
Change between placebo salmeterol and active salmeterol for AM 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
Population: An intention-to-treat (ITT) paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Morning (AM) Peak Expiratory Flow (PEF) Rate | -21 liters per minute |
| B16 Gly/Gly | Morning (AM) Peak Expiratory Flow (PEF) Rate | -22 liters per minute |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design. A sample size of 40 participants per genotype was required to detect a difference of 25 L/min in AM PEF (and relevant effect sizes for secondary outcomes) with a two-sided, 0.05 significance level test with 90% statistical power and a 15% drop-out rate.p-value: 0.9995% CI: [-14, 14]Mixed Models Analysis
Secondary
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).
Time frame: Clinic visits at weeks 0 and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Asthma Control Questionnaire (ACQ) | 0.13 units on a scale |
| B16 Gly/Gly | Asthma Control Questionnaire (ACQ) | 0.11 units on a scale |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.8995% CI: [-0.23, 0.26]Mixed Models Analysis
Secondary
Asthma Symptoms
Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).
Time frame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| B16 Arg/Arg | Asthma Symptoms | 0.04 units on a scale |
| B16 Gly/Gly | Asthma Symptoms | 0.00 units on a scale |
Comparison: A mixed-effects linear model was attempted but could not converge because very few symptoms were recorded, so a nonparametric analysis was applied.p-value: 0.0995% CI: [-0.02, 0.07]Wilcoxon (Mann-Whitney)
Secondary
Evening (PM) Peak Expiratory Flow (PEF) Rate
Change between placebo salmeterol and active salmeterol for PM 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
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Evening (PM) Peak Expiratory Flow (PEF) Rate | -25 liters per minute |
| B16 Gly/Gly | Evening (PM) Peak Expiratory Flow (PEF) Rate | -24 liters per minute |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.8295% CI: [-15, 12]Mixed Models Analysis
Secondary
Exhaled Breath Condensate (EBC)
Change between placebo salmeterol and active salmeterol for EBC
Time frame: Clinic visits at weeks 0, 10, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Exhaled Breath Condensate (EBC) | -0.10 pH |
| B16 Gly/Gly | Exhaled Breath Condensate (EBC) | -0.03 pH |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.7995% CI: [-0.56, 0.43]Mixed Models Analysis
Secondary
Exhaled Nitric Oxide (eNO)
Change between placebo salmeterol and active salmeterol for eNO
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| B16 Arg/Arg | Exhaled Nitric Oxide (eNO) | 0.12 parts per billion |
| B16 Gly/Gly | Exhaled Nitric Oxide (eNO) | -0.02 parts per billion |
Comparison: A mixed-effects linear model was applied to the natural logarithm of eNO to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.1395% CI: [-0.04, 0.31]Mixed Models Analysis
Secondary
Methacholine Provocative Concentration 20 (PC20)
Change between placebo salmeterol and active salmeterol for methacholine PC20
Time frame: Clinic visits at weeks 0 and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| B16 Arg/Arg | Methacholine Provocative Concentration 20 (PC20) | 0.06 milligrams per milliliter |
| B16 Gly/Gly | Methacholine Provocative Concentration 20 (PC20) | -1.27 milligrams per milliliter |
Comparison: A mixed-effects linear model was applied to the base-2 logarithm of the methacholine PC20 to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.00495% CI: [0.43, 2.21]Mixed Models Analysis
Secondary
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)
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
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Peak Expiratory Flow (PEF) Variability | 0.2 percentage |
| B16 Gly/Gly | Peak Expiratory Flow (PEF) Variability | 0.7 percentage |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.3195% CI: [-1.6, 0.5]Mixed Models Analysis
Secondary
Rescue Medication (Ipratropium and Albuterol) Use
Change between placebo salmeterol and active salmeterol for rescue medication 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
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| B16 Arg/Arg | Rescue Medication (Ipratropium and Albuterol) Use | 0.2 puffs per day |
| B16 Gly/Gly | Rescue Medication (Ipratropium and Albuterol) Use | 0.0 puffs per day |
Comparison: A mixed-effects linear model was attempted but could not converge because very few usages of rescue medications were recorded, so a nonparametric analysis was applied.p-value: 0.2595% CI: [-0.1, 0.2]Wilcoxon (Mann-Whitney)
Secondary
Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator | -0.08 liters |
| B16 Gly/Gly | Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator | -0.04 liters |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.3495% CI: [-0.1, 0.03]Mixed Models Analysis
Secondary
Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator | -0.04 liters |
| B16 Gly/Gly | Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator | -0.03 liters |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.9195% CI: [-0.08, 0.07]Mixed Models Analysis
Secondary
Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Population: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| B16 Arg/Arg | Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator | -17 liters per minute |
| B16 Gly/Gly | Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator | -17 liters per minute |
Comparison: A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.p-value: 0.9395% CI: [-15, 14]Mixed Models Analysis