Trial Outcomes & Findings for Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE) (NCT NCT00200967)
NCT ID: NCT00200967
Last Updated: 2018-01-23
Results Overview
Change between placebo salmeterol and active salmeterol for AM PEF rate
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
87 participants
Primary outcome 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
Results posted on
2018-01-23
Participant Flow
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.
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).
Participant milestones
| Measure |
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
|
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
|
|---|---|---|
|
First Treatment Period
STARTED
|
42
|
45
|
|
First Treatment Period
First Treatment Period
|
42
|
45
|
|
First Treatment Period
COMPLETED
|
36
|
44
|
|
First Treatment Period
NOT COMPLETED
|
6
|
1
|
|
Wash-out Period
STARTED
|
36
|
44
|
|
Wash-out Period
COMPLETED
|
36
|
43
|
|
Wash-out Period
NOT COMPLETED
|
0
|
1
|
|
Second Treatment Period
STARTED
|
36
|
43
|
|
Second Treatment Period
COMPLETED
|
35
|
41
|
|
Second Treatment Period
NOT COMPLETED
|
1
|
2
|
|
Run-out Period
STARTED
|
35
|
41
|
|
Run-out Period
COMPLETED
|
34
|
41
|
|
Run-out Period
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
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
|
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
|
|---|---|---|
|
First Treatment Period
Withdrawal by Subject
|
5
|
1
|
|
First Treatment Period
Pregnancy
|
1
|
0
|
|
Wash-out Period
Lost to Follow-up
|
0
|
1
|
|
Second Treatment Period
Withdrawal by Subject
|
1
|
2
|
|
Run-out Period
Lost to Follow-up
|
1
|
0
|
Baseline Characteristics
Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)
Baseline characteristics by cohort
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
Total
n=87 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
42 Participants
n=5 Participants
|
45 Participants
n=7 Participants
|
87 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Continuous
|
39 years
STANDARD_DEVIATION 11 • n=5 Participants
|
42 years
STANDARD_DEVIATION 12 • n=7 Participants
|
41 years
STANDARD_DEVIATION 12 • n=5 Participants
|
|
Sex: Female, Male
Female
|
32 Participants
n=5 Participants
|
29 Participants
n=7 Participants
|
61 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
42 participants
n=5 Participants
|
45 participants
n=7 Participants
|
87.0 participants
n=5 Participants
|
PRIMARY outcome
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 periodPopulation: 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.
Change between placebo salmeterol and active salmeterol for AM PEF rate
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Morning (AM) Peak Expiratory Flow (PEF) Rate
|
-21 liters per minute
Interval -31.0 to -12.0
|
-22 liters per minute
Interval -32.0 to -11.0
|
SECONDARY outcome
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 periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for PM PEF rate
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Evening (PM) Peak Expiratory Flow (PEF) Rate
|
-25 liters per minute
Interval -34.0 to -16.0
|
-24 liters per minute
Interval -34.0 to -14.0
|
SECONDARY outcome
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 periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for PEF variability, where PEF variability is defined as 100% x (PM PEF - AM PEF)/(PM PEF)
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Peak Expiratory Flow (PEF) Variability
|
0.2 percentage
Interval -0.6 to 1.0
|
0.7 percentage
Interval 0.0 to 1.4
|
SECONDARY outcome
Timeframe: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Asthma Symptoms
|
0.04 units on a scale
Interval 0.0 to 0.12
|
0.00 units on a scale
Interval -0.01 to 0.02
|
SECONDARY outcome
Timeframe: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for rescue medication use
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Rescue Medication (Ipratropium and Albuterol) Use
|
0.2 puffs per day
Interval 0.0 to 0.5
|
0.0 puffs per day
Interval 0.0 to 0.2
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
|
-0.08 liters
Interval -0.13 to -0.03
|
-0.04 liters
Interval -0.09 to 0.0
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
|
-0.04 liters
Interval -0.08 to 0.01
|
-0.03 liters
Interval -0.09 to 0.03
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
|
-17 liters per minute
Interval -27.0 to -8.0
|
-17 liters per minute
Interval -27.0 to -6.0
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for eNO
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Exhaled Nitric Oxide (eNO)
|
0.12 parts per billion
Interval -0.01 to 0.24
|
-0.02 parts per billion
Interval -0.15 to 0.11
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0, 10, and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for EBC
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Exhaled Breath Condensate (EBC)
|
-0.10 pH
Interval -0.45 to 0.26
|
-0.03 pH
Interval -0.37 to 0.31
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0 and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for methacholine PC20
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Methacholine Provocative Concentration 20 (PC20)
|
0.06 milligrams per milliliter
Interval -0.6 to 0.71
|
-1.27 milligrams per milliliter
Interval -1.87 to -0.66
|
SECONDARY outcome
Timeframe: Clinic visits at weeks 0 and 18 of each treatment periodPopulation: An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control).
Outcome measures
| Measure |
B16 Arg/Arg
n=42 Participants
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
|
B16 Gly/Gly
n=45 Participants
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
|
|---|---|---|
|
Asthma Control Questionnaire (ACQ)
|
0.13 units on a scale
Interval -0.06 to 0.32
|
0.11 units on a scale
Interval -0.04 to 0.26
|
Adverse Events
B16 Arg/Arg
Serious events: 1 serious events
Other events: 20 other events
Deaths: 0 deaths
B16 Gly/Gly
Serious events: 4 serious events
Other events: 20 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
B16 Arg/Arg
n=42 participants at risk
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
|
B16 Gly/Gly
n=45 participants at risk
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
|
|---|---|---|
|
General disorders
hospitalization
|
0.00%
0/42 • 1 year
does not differ from clinicaltrials.gov definitions
|
2.2%
1/45 • Number of events 1 • 1 year
does not differ from clinicaltrials.gov definitions
|
|
Psychiatric disorders
hospitalization
|
2.4%
1/42 • Number of events 1 • 1 year
does not differ from clinicaltrials.gov definitions
|
6.7%
3/45 • Number of events 3 • 1 year
does not differ from clinicaltrials.gov definitions
|
Other adverse events
| Measure |
B16 Arg/Arg
n=42 participants at risk
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
|
B16 Gly/Gly
n=45 participants at risk
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
|
|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
respiratory infection
|
47.6%
20/42 • Number of events 100 • 1 year
does not differ from clinicaltrials.gov definitions
|
44.4%
20/45 • Number of events 98 • 1 year
does not differ from clinicaltrials.gov definitions
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place