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

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ClinicalTrials.gov Identifier: NCT00200967
Recruitment Status : Completed
First Posted : September 20, 2005
Results First Posted : June 2, 2009
Last Update Posted : January 23, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Asthma Clinical Research Network
Information provided by (Responsible Party):
Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Asthma
Interventions Drug: salmeterol
Drug: beclomethasone HFA
Enrollment 87
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).
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description 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 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
Period Title: First Treatment Period
Started 42 45
First Treatment Period 42 45
Completed 36 44
Not Completed 6 1
Reason Not Completed
Withdrawal by Subject             5             1
Pregnancy             1             0
Period Title: Wash-out Period
Started 36 44
Completed 36 43
Not Completed 0 1
Reason Not Completed
Lost to Follow-up             0             1
Period Title: Second Treatment Period
Started 36 43
Completed 35 41
Not Completed 1 2
Reason Not Completed
Withdrawal by Subject             1             2
Period Title: Run-out Period
Started 35 41
Completed 34 41
Not Completed 1 0
Reason Not Completed
Lost to Follow-up             1             0
Arm/Group Title B16 Arg/Arg B16 Gly/Gly Total
Hide Arm/Group Description 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 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 of all reporting groups
Overall Number of Baseline Participants 42 45 87
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 45 participants 87 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
42
 100.0%
45
 100.0%
87
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 42 participants 45 participants 87 participants
39  (11) 42  (12) 41  (12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 45 participants 87 participants
Female
32
  76.2%
29
  64.4%
61
  70.1%
Male
10
  23.8%
16
  35.6%
26
  29.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 42 participants 45 participants 87 participants
42 45 87
1.Primary Outcome
Title Morning (AM) Peak Expiratory Flow (PEF) Rate
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters per minute
-21
(-31 to -12)
-22
(-32 to -11)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0
Confidence Interval 95%
-14 to 14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for AM PEF rate.
2.Secondary Outcome
Title Evening (PM) Peak Expiratory Flow (PEF) Rate
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters per minute
-25
(-34 to -16)
-24
(-34 to -14)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1
Confidence Interval 95%
-15 to 12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for PM PEF rate.
3.Secondary Outcome
Title Peak Expiratory Flow (PEF) Variability
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage
0.2
(-0.6 to 1.0)
0.7
(0.0 to 1.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.31
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.6
Confidence Interval 95%
-1.6 to 0.5
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.5
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for PEF variability.
4.Secondary Outcome
Title Asthma Symptoms
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.04
(0.00 to 0.12)
0.00
(-0.01 to 0.02)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was attempted but could not converge because very few symptoms were recorded, so a nonparametric analysis was applied.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval 95%
-0.02 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.02
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for asthma symptoms.
5.Secondary Outcome
Title Rescue Medication (Ipratropium and Albuterol) Use
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Mean (95% Confidence Interval)
Unit of Measure: puffs per day
0.2
(0.0 to 0.5)
0.0
(0.0 to 0.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.25
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0
Confidence Interval 95%
-0.1 to 0.2
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for rescue medication use.
6.Secondary Outcome
Title Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters
-0.08
(-0.13 to -0.03)
-0.04
(-0.09 to 0.00)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.34
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.03
Confidence Interval 95%
-0.10 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.03
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator.
7.Secondary Outcome
Title Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters
-0.04
(-0.08 to 0.01)
-0.03
(-0.09 to 0.03)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.91
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval 95%
-0.08 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.03
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator.
8.Secondary Outcome
Title Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters per minute
-17
(-27 to -8)
-17
(-27 to -6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.93
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1
Confidence Interval 95%
-15 to 14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator.
9.Secondary Outcome
Title Exhaled Nitric Oxide (eNO)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Geometric Mean (95% Confidence Interval)
Unit of Measure: parts per billion
0.12
(-0.01 to 0.24)
-0.02
(-0.15 to 0.11)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.13
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.14
Confidence Interval 95%
-0.04 to 0.31
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.08
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for eNO.
10.Secondary Outcome
Title Exhaled Breath Condensate (EBC)
Hide Description Change between placebo salmeterol and active salmeterol for EBC
Time Frame Clinic visits at weeks 0, 10, and 18 of each treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pH
-0.10
(-0.45 to 0.26)
-0.03
(-0.37 to 0.31)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.79
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.07
Confidence Interval 95%
-0.56 to 0.43
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.24
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for EBC.
11.Secondary Outcome
Title Methacholine Provocative Concentration 20 (PC20)
Hide Description Change between placebo salmeterol and active salmeterol for methacholine PC20
Time Frame Clinic visits at weeks 0 and 18 of each treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Geometric Mean (95% Confidence Interval)
Unit of Measure: milligrams per milliliter
0.06
(-0.60 to 0.71)
-1.27
(-1.87 to -0.66)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.32
Confidence Interval 95%
0.43 to 2.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.45
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for methacholine PC20.
12.Secondary Outcome
Title Asthma Control Questionnaire (ACQ)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
An ITT paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description:
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 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
Overall Number of Participants Analyzed 42 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.13
(-0.06 to 0.32)
0.11
(-0.04 to 0.26)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection B16 Arg/Arg, B16 Gly/Gly
Comments A mixed-effects linear model was applied to account for the repeated measurements within each treatment period of the crossover design.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.89
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval 95%
-0.23 to 0.26
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.12
Estimation Comments The comparison represents the difference between Arg/Arg and Gly/Gly participants based on the change between placebo salmeterol and active salmeterol for ACQ.
Time Frame 1 year
Adverse Event Reporting Description does not differ from clinicaltrials.gov definitions
 
Arm/Group Title B16 Arg/Arg B16 Gly/Gly
Hide Arm/Group Description 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 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
All-Cause Mortality
B16 Arg/Arg B16 Gly/Gly
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
B16 Arg/Arg B16 Gly/Gly
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/42 (2.38%)      4/45 (8.89%)    
General disorders     
hospitalization   0/42 (0.00%)  0 1/45 (2.22%)  1
Psychiatric disorders     
hospitalization   1/42 (2.38%)  1 3/45 (6.67%)  3
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
B16 Arg/Arg B16 Gly/Gly
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   20/42 (47.62%)      20/45 (44.44%)    
Respiratory, thoracic and mediastinal disorders     
respiratory infection   20/42 (47.62%)  100 20/45 (44.44%)  98
Indicates events were collected by systematic assessment
The study used a moderately high dose of ICS. Genotype-specific effects may be evident at lower doses of ICS often used in combination therapy. Also, short-acting β2-agonists have been shown to have genotype-specific effects on asthma outcomes.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Vernon M. Chinchilli
Organization: Penn State College of Medicine
Phone: 717-531-4262
Responsible Party: Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT00200967     History of Changes
Other Study ID Numbers: 262
5U10HL074231 ( U.S. NIH Grant/Contract )
U10HL074073 ( U.S. NIH Grant/Contract )
U10HL074204 ( U.S. NIH Grant/Contract )
U10HL074208 ( U.S. NIH Grant/Contract )
U10HL074212 ( U.S. NIH Grant/Contract )
U10HL074218 ( U.S. NIH Grant/Contract )
U10HL074225 ( U.S. NIH Grant/Contract )
U10HL074227 ( U.S. NIH Grant/Contract )
U10HL074231 ( U.S. NIH Grant/Contract )
First Submitted: September 12, 2005
First Posted: September 20, 2005
Results First Submitted: March 5, 2009
Results First Posted: June 2, 2009
Last Update Posted: January 23, 2018