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

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00200967
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Asthma Clinical Research Network (Other)
• Enrollment: 87
• Locations: 7
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 12.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: salmeterol; Drug: beclomethasone HFA	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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	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
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	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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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)

3. 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).

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92103
2	University of California, San Francisco	San Francisco	California	United States	94143-0130
3	National Jewish Medical & Research Center	Denver	Colorado	United States	80206
4	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
5	Washington University	Saint Louis	Missouri	United States	63110
6	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27103
7	University of Wisconsin Madison	Madison	Wisconsin	United States	53792-3244

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• National Heart, Lung, and Blood Institute (NHLBI)
• Asthma Clinical Research Network

Investigators

• Principal Investigator: Homer Boushey, University of California, San Francisco
• Principal Investigator: Mario Castro, Washington University School of Medicine
• Principal Investigator: Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center
• Principal Investigator: Elliot Israel, Brigham and Women's Hospital
• Principal Investigator: Robert Lemanske, University of Wisconsin, Madison
• Principal Investigator: Richard Martin, National Jewish Medical & Research Center
• Principal Investigator: Stephen Peters, Wake Forest University Health Sciences
• Principal Investigator: Stephen Wasserman, University of California, San Diego

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Asthma Clinical Research Network (ACRN) Website

Publications

None provided.

• Responsible Party: Vernon M. Chinchilli, PhD, Professor and Chair, Department of Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00200967
• Other Study ID Numbers: 262; 5U10HL074231; U10HL074073; U10HL074204; U10HL074208; U10HL074212; U10HL074218; U10HL074225; U10HL074227; U10HL074231
• First Posted: Sep 20, 2005
• Last Update Posted: Jan 23, 2018
• Last Verified: Dec 1, 2017

• Additional relevant MeSH terms: Asthma; Beclomethasone; Salmeterol Xinafoate

Study Results

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 Detail	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
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
Period Title: First Treatment Period
STARTED	36	44
COMPLETED	36	43
NOT COMPLETED	0	1
Period Title: First Treatment Period
STARTED	36	43
COMPLETED	35	41
NOT COMPLETED	1	2
Period Title: First Treatment Period
STARTED	35	41
COMPLETED	34	41
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	B16 Arg/Arg	B16 Gly/Gly	Total
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 Participants	42	45	87
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	42 100%	45 100%	87 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39 (11)	42 (12)	41 (12)
Sex: Female, Male (Count of Participants)
Female	32 76.2%	29 64.4%	61 70.1%
Male	10 23.8%	16 35.6%	26 29.9%
Region of Enrollment (participants) [Number]
United States	42 100%	45 100%	87.0 100%

Outcome Measures

1. Primary Outcome

Title	Morning (AM) Peak Expiratory Flow (PEF) Rate
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [liters per minute]	-21	-22

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
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Mixed Models Analysis
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [liters per minute]	-25	-24

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
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Mixed Models Analysis
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [percentage]	0.2	0.7

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
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Mixed Models Analysis
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Mean (95% Confidence Interval) [units on a scale]	0.04	0.00

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
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Mean (95% Confidence Interval) [puffs per day]	0.2	0.0

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
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [liters]	-0.08	-0.04

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
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Mixed Models Analysis
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [liters]	-0.04	-0.03

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
Statistical Test of Hypothesis	p-Value	0.91
	Comments
	Method	Mixed Models Analysis
	Comments
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
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [liters per minute]	-17	-17

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
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Mixed Models Analysis
	Comments
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)
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

Outcome Measure Data

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
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
Measure Participants	42	45
Geometric Mean (95% Confidence Interval) [parts per billion]	0.12	-0.02

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
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Mixed Models Analysis
	Comments
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)
Description	Change between placebo salmeterol and active salmeterol for EBC
Time Frame	Clinic visits at weeks 0, 10, and 18 of each treatment period

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [pH]	-0.10	-0.03

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
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Mixed Models Analysis
	Comments
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)
Description	Change between placebo salmeterol and active salmeterol for methacholine PC20
Time Frame	Clinic visits at weeks 0 and 18 of each treatment period

Outcome Measure Data

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
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
Measure Participants	42	45
Geometric Mean (95% Confidence Interval) [milligrams per milliliter]	0.06	-1.27

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
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
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)
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

Outcome Measure Data

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
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
Measure Participants	42	45
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.13	0.11

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
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Mixed Models Analysis
	Comments
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.

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	does not differ from clinicaltrials.gov definitions
Arm/Group Title	B16 Arg/Arg		B16 Gly/Gly
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	B16 Arg/Arg		B16 Gly/Gly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)		4/45 (8.9%)
General disorders
hospitalization	0/42 (0%)	0	1/45 (2.2%)	1
Psychiatric disorders
hospitalization	1/42 (2.4%)	1	3/45 (6.7%)	3
Other (Not Including Serious) Adverse Events
	B16 Arg/Arg		B16 Gly/Gly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/42 (47.6%)		20/45 (44.4%)
Respiratory, thoracic and mediastinal disorders
respiratory infection	20/42 (47.6%)	100	20/45 (44.4%)	98

Limitations/Caveats

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.

More Information

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.