A study in asthmatic children (6 to <12 yrs) comparing single doses of formoterol and Foradil® evaluating efficacy - CHASE 2

Study identifier:D589GC00002

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 2, randomized, blinded, 5-period cross-over, placebo and active-controlled, multicenter, dose-finding study of single doses of formoterol 2.25 µg, 4.5 µg, and 9 µg delivered via Symbicort® pressurized metered-dose inhaler (pMDI) and Foradil® Aerolizer® 12 µg evaluating the bronchodilating effects and safety in children, ages 6 to <12 years, with asthma who are receiving background treatment with budesonide pMDI 160 ug bid

Medical condition

asthma

Phase

Phase 2

Healthy volunteers

Study drug

80/2.25 μg Symbicort pMDI, 80/4.5 μg Symbicort pMDI, Foradil Aerolizer 12 μg, 40 μg budesonide HFA pMDI, placebo HFA pMDI, 80 μg budesonide HFA pMDI

Sex

All

Actual Enrollment

Study type

Interventional

Age

6 Years - 11 Years

Date

Study Start Date: 01 Sept 2010

Primary Completion Date: 01 Dec 2011

Study Completion Date: 01 Dec 2011

Study design

Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2014 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

KRUGERSDORP, Gauteng, South Africa

Location

Research Site

ALTOONA, PA, United States

Location

Research Site

BUDAPEST, Hungary

Location

Research Site

CAPE TOWN, SOUTH AFRICA, South Africa

Location

Research Site

CAPE TOWN, W CAPE, South Africa

Location

Research Site

CHARLESTON, SC, United States

Location

Research Site

CLAREMONT, W CAPE, South Africa

Location

Research Site

DUBLIN, Bulgaria

Arms	Assigned Interventions
Experimental: BUD 160/FM 2.25 2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI × 1 inhalation) + 40 μg budesonide (BUD)hydrofluoroalkane (HFA) pMDI × 2 inhalations	Drug: 80/2.25 μg Symbicort pMDI inhalation Drug: 40 μg budesonide HFA pMDI inhalation
Experimental: BUD 160/FM 4.5 placebo HFA pMDI × 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI × 2 inhalations)	Drug: 80/2.25 μg Symbicort pMDI inhalation Drug: placebo HFA pMDI inhalation
Experimental: BUD 160/FM 9.0 placebo HFA pMDI × 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI × 2 inhalations)	Drug: 80/4.5 μg Symbicort pMDI inhalation Drug: placebo HFA pMDI inhalation
Placebo Comparator: BUD 160 placebo HFA pMDI × 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations	Drug: 40 μg budesonide HFA pMDI inhalation Drug: placebo HFA pMDI inhalation Drug: 80 μg budesonide HFA pMDI inhalation
Active Comparator: BUD 160/Foradil 12.0 Foradil Aerolizer 12 μg × 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations	Drug: Foradil Aerolizer 12 μg inhalation Drug: 40 μg budesonide HFA pMDI inhalation Drug: 80 μg budesonide HFA pMDI inhalation

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This multicenter study was conducted in Europe and the United States between 7 October 2010 and 3 January 2012.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study consisted of a screening visit, an enrolment visit, a 1- to 2-week run-in (standardization) period, randomization at Visit 3, and 4 further visits (Visits 4-7)separated by approximately 7-day (minimum 3 days; maximum 14 days) wash-out (stabilization) periods. Subjects received 1 of 5 single-dose treatments at Visits 3-7, in random order.

Reporting Groups

	Description
Randomized patients	All randomized patients

Participant Flow for 10 periods

Period 1: BUD 160/FM 2.25 (1 dose)

	Randomized patients
STARTED	54
COMPLETED	54
NOT COMPLETED	0

Period 2: Washout after BUD 160/FM 2.25 (7 days)

	Randomized patients
STARTED	54
COMPLETED	53
NOT COMPLETED	1
Withdrawal by Subject	1

Period 3: BUD 160/FM 4.5 (1 dose)

	Randomized patients
STARTED	53
COMPLETED	53
NOT COMPLETED	0

Period 4: Washout after BUD 160/FM 4.5 (7 days)

	Randomized patients
STARTED	53
COMPLETED	52
NOT COMPLETED	1
Adverse Event	1

Period 5: BUD 160/FM 9.0 (1 dose)

	Randomized patients
STARTED	53
COMPLETED	53
NOT COMPLETED	0

Period 6: Washout after BUD 160/FM 9.0 (7 days)

	Randomized patients
STARTED	53
COMPLETED	51
NOT COMPLETED	2
Withdrawal by Subject	1
Adverse Event	1

Period 7: BUD 160 (1 dose)

	Randomized patients
STARTED	51
COMPLETED	51
NOT COMPLETED	0

Period 8: Washout after BUD 160 (7 days)

	Randomized patients
STARTED	51
COMPLETED	51
NOT COMPLETED	0

Period 9: BUD 160/ Foradil 12.0 (1 dose)

	Randomized patients
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Period 10: Washout after BUD 160/ Foradil (7 days)

	Randomized patients
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Randomized patients	All randomized patients

Baseline Measures

	Randomized patients
Number of Participants [units: Participants]	54
Age Continuous [units: years] Mean ± Standard Deviation	9.2 ± 1.79
Age, Customized [units: participants]
>=6 to <8 years	11
>=8 to < 12 years	43
Gender, Male/Female [units: participants]
Female	23
Male	31
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	22
White	31
More than one race	0
Unknown or Not Reported	1

Outcome Measures

1. Primary Outcome Measure: Average 12 hour forced expiratory volume in 1 second (FEV1) [ Time Frame: at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose ]

Measure Type	Primary
Measure Name	Average 12 hour forced expiratory volume in 1 second (FEV1)
Measure Description	Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was obtained from the full expiratory flow-volume-time curve. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. Twelve-hour serial FEV1 was calculated through an AUC determination and then divided by time, so that the final value is expressed in liters. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time Frame	at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160	placebo HFA pMDI x 1 inhalation + 80 μg budesonide HFA pMDI x 2 inhalations
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Measured Values

	BUD 160/FM 2.25	BUD 160/FM 4.5	BUD 160/FM 9.0	BUD 160	BUD 160/ Foradil 12.0
Number of Participants Analyzed [units:participants]	54	53	53	51	51
Average 12 hour forced expiratory volume in 1 second (FEV1) [units: liters] Least Squares Mean (Standard Error)	1.546 (0.0097)	1.594 (0.0099)	1.603 (0.0099)	1.489 (0.0101)	1.603 (0.0101)

Statistical Analysis 1 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 9.0, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.114
Standard Error of the mean	± 0.0140
95% Confidence Interval	( 0.087 to 0.142 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 4.5, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.105
Standard Error of the mean	± 0.0140
95% Confidence Interval	( 0.078 to 0.133 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 2.25, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Other^[5]	0.058
Standard Error of the mean	± 0.0141
95% Confidence Interval	( 0.030 to 0.085 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 4.5, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.5223
Other^[5]	-0.009
Standard Error of the mean	± 0.0139
95% Confidence Interval	( -0.036 to 0.018 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Other^[5]	-0.057
Standard Error of the mean	± 0.0139
95% Confidence Interval	( -0.084 to -0.029 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 4.5
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0007
Other^[5]	-0.048
Standard Error of the mean	± 0.0138
95% Confidence Interval	( -0.075 to -0.020 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-0.114
Standard Error of the mean	± 0.0141
95% Confidence Interval	( -0.142 to -0.086 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 2.25, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Other^[5]	-0.056
Standard Error of the mean	± 0.0141
95% Confidence Interval	( -0.084 to -0.028 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 4.5, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.5394
Other^[5]	-0.009
Standard Error of the mean	± 0.0141
95% Confidence Interval	( -0.036 to 0.019 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Average 12 hour forced expiratory volume in 1 second (FEV1)

Groups^[1]	BUD 160/FM 9.0, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.9863
Other^[5]	0.000
Standard Error of the mean	± 0.0140
95% Confidence Interval	( -0.027 to 0.028 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: FEV1 at 12 hours after study medication inhalation [ Time Frame: 12 hours after dosing ]

Measure Type	Secondary
Measure Name	FEV1 at 12 hours after study medication inhalation
Measure Description	Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. The FEV1 value at 12 hours after dosing was taken as the 12-hour measurement (720 minutes) from the serial spirometry. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time Frame	12 hours after dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160	placebo HFA pMDI x 1 inhalation + 80 μg budesonide HFA pMDI x 2 inhalations
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Measured Values

	BUD 160/FM 2.25	BUD 160/FM 4.5	BUD 160/FM 9.0	BUD 160	BUD 160/ Foradil 12.0
Number of Participants Analyzed [units:participants]	54	53	53	51	51
FEV1 at 12 hours after study medication inhalation [units: liters] Least Squares Mean (Standard Error)	1.641 (0.0175)	1.692 (0.0177)	1.731 (0.0177)	1.626 (0.0181)	1.709 (0.0182)

Statistical Analysis 1 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 9.0, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.105
Standard Error of the mean	± 0.0250
95% Confidence Interval	( 0.056 to 0.155 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 4.5, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0092
Other^[5]	0.066
Standard Error of the mean	± 0.0252
95% Confidence Interval	( 0.017 to 0.116 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 2.25, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.5509
Other^[5]	0.015
Standard Error of the mean	± 0.0252
95% Confidence Interval	( -0.035 to 0.065 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 4.5, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.1163
Other^[5]	-0.039
Standard Error of the mean	± 0.0249
95% Confidence Interval	( -0.088 to 0.010 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0004
Other^[5]	-0.090
Standard Error of the mean	± 0.0250
95% Confidence Interval	( -0.140 to -0.041 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 4.5
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0400
Other^[5]	-0.051
Standard Error of the mean	± 0.0247
95% Confidence Interval	( -0.100 to -0.002 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0011
Other^[5]	-0.083
Standard Error of the mean	± 0.0252
95% Confidence Interval	( -0.133 to -0.034 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 2.25, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0077
Other^[5]	-0.068
Standard Error of the mean	± 0.0254
95% Confidence Interval	( -0.118 to -0.018 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 4.5, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.4957
Other^[5]	-0.017
Standard Error of the mean	± 0.0252
95% Confidence Interval	( -0.067 to 0.033 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for FEV1 at 12 hours after study medication inhalation

Groups^[1]	BUD 160/FM 9.0, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.3800
Other^[5]	0.022
Standard Error of the mean	± 0.0250
95% Confidence Interval	( -0.027 to 0.071 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	LOCF was performed if missing data were post last non-missing post-baseline assessment.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Maximal FEV1 during the 12-hour study period [ Time Frame: at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose ]

Measure Type	Secondary
Measure Name	Maximal FEV1 during the 12-hour study period
Measure Description	Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. The maximum FEV1 value was defined as the largest observed FEV1 value recorded during each 12-hour serial spirometry procedure. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time Frame	at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160	placebo HFA pMDI x 1 inhalation + 80 μg budesonide HFA pMDI x 2 inhalations
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Measured Values

	BUD 160/FM 2.25	BUD 160/FM 4.5	BUD 160/FM 9.0	BUD 160	BUD 160/ Foradil 12.0
Number of Participants Analyzed [units:participants]	54	53	53	51	51
Maximal FEV1 during the 12-hour study period [units: liters] Least Squares Mean (Standard Error)	1.833 (0.0119)	1.889 (0.0120)	1.884 (0.0120)	1.777 (0.0123)	1.892 (0.0123)

Statistical Analysis 1 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 9.0, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.107
Standard Error of the mean	± 0.0170
95% Confidence Interval	( 0.073 to 0.140 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 4.5, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.112
Standard Error of the mean	± 0.0171
95% Confidence Interval	( 0.078 to 0.146 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 2.25, BUD 160
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0011
Other^[5]	0.057
Standard Error of the mean	± 0.0172
95% Confidence Interval	( 0.023 to 0.090 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 4.5, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.7589
Other^[5]	0.005
Standard Error of the mean	± 0.0169
95% Confidence Interval	( -0.028 to 0.039 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0035
Other^[5]	-0.050
Standard Error of the mean	± 0.0170
95% Confidence Interval	( -0.084 to -0.017 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 4.5
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0011
Other^[5]	-0.055
Standard Error of the mean	± 0.0168
95% Confidence Interval	( -0.089 to -0.022 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-0.115
Standard Error of the mean	± 0.0171
95% Confidence Interval	( -0.149 to -0.081 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 2.25, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0008
Other^[5]	-0.058
Standard Error of the mean	± 0.0172
95% Confidence Interval	( -0.092 to -0.024 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 4.5, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.8582
Other^[5]	-0.003
Standard Error of the mean	± 0.0172
95% Confidence Interval	( -0.037 to 0.031 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Maximal FEV1 during the 12-hour study period

Groups^[1]	BUD 160/FM 9.0, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.6276
Other^[5]	-0.008
Standard Error of the mean	± 0.0170
95% Confidence Interval	( -0.042 to 0.025 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Urinary excretion of formoterol during the 12 hours following inhalation of study drug [ Time Frame: 0 to 12 hours ]

Measure Type	Secondary
Measure Name	Urinary excretion of formoterol during the 12 hours following inhalation of study drug
Measure Description	The amount of formoterol excreted unchanged in urine over the 12-hour period after administration [Ae(0-12h)] was calculated from the concentration of formoterol in urine multiplied by the total volume of urine collected. Volume was determined from the weight of the collected urine times an assumed urine density of 1020 g/L. The data for six patients who did not have measurable formoterol in their urine on the Foradil 12 μg treatment day was excluded from the analysis. All other urine concentrations below the lower limit of quantification were set to zero. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time Frame	0 to 12 hours
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Measured Values

	BUD 160/FM 2.25	BUD 160/FM 4.5	BUD 160/FM 9.0	BUD 160/ Foradil 12.0
Number of Participants Analyzed [units:participants]	51	52	51	43
Urinary excretion of formoterol during the 12 hours following inhalation of study drug [units: pmol] Least Squares Mean (95% Confidence Interval)	192.0 (156.36 to 235.88)	366.3 (298.85 to 448.96)	740.6 (602.45 to 910.51)	658.7 (522.61 to 830.24)

Statistical Analysis 1 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 4.5
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.0001
Other^[5]	0.52
95% Confidence Interval	( 0.393 to 0.700 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 2.25, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.0001
Other^[5]	0.26
95% Confidence Interval	( 0.194 to 0.347 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 2.25, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.0001
Other^[5]	0.29
95% Confidence Interval	( 0.214 to 0.396 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 4.5, BUD 160/FM 9.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.0001
Other^[5]	0.49
95% Confidence Interval	( 0.371 to 0.659 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 4.5, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.0002
Other^[5]	0.56
95% Confidence Interval	( 0.409 to 0.755 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Urinary excretion of formoterol during the 12 hours following inhalation of study drug

Groups^[1]	BUD 160/FM 9.0, BUD 160/ Foradil 12.0
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.4512
Other^[5]	1.12
95% Confidence Interval	( 0.827 to 1.528 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Factors in the ANOVA model included: patient, period and treatment.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	A shift log transformation was performed on the response variable in the ANOVA model, using log(response) [log(response + 1) if response is 0].
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional Description	One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160	placebo HFA pMDI x 1 inhalation + 80 μg budesonide HFA pMDI x 2 inhalations
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Serious Adverse Events

	BUD 160/FM 2.25	BUD 160/FM 4.5	BUD 160/FM 9.0	BUD 160	BUD 160/ Foradil 12.0
Total, serious adverse events
# participants affected / at risk	0/54 (0.00%)	0/53 (0.00%)	0/53 (0.00%)	0/51 (0.00%)	0/50 (0.00%)

Other Adverse Events

Time Frame	No text entered.
Additional Description	One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
BUD 160/FM 2.25	2.25 μg formoterol (as 80/2.25 μg Symbicort pMDI x 1 inhalation) + 40 μg budesonide HFA pMDI × 2 inhalations
BUD 160/FM 4.5	placebo HFA pMDI x 1 inhalation + 4.5 μg formoterol (as 80/2.25 μg Symbicort pMDI x 2 inhalations)
BUD 160/FM 9.0	placebo HFA pMDI x 1 inhalation + 9 μg formoterol (as 80/4.5 μg Symbicort pMDI x 2 inhalations)
BUD 160	placebo HFA pMDI x 1 inhalation + 80 μg budesonide HFA pMDI x 2 inhalations
BUD 160/ Foradil 12.0	Foradil Aerolizer 12 μg x 1 inhalation + 80 μg budesonide HFA pMDI × 2 inhalations

Other Adverse Events

BUD 160/FM 2.25

BUD 160/FM 4.5

BUD 160/FM 9.0

BUD 160

BUD 160/ Foradil 12.0

Total, other (not including serious) adverse events

# participants affected / at risk

1/54 (1.85%)

1/53 (1.89%)

5/53 (9.43%)

2/51 (3.92%)

0/50 (0.00%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/54 (1.85%)

1/53 (1.89%)

5/53 (9.43%)

2/51 (3.92%)

0/50 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 14.1
2	Term from vocabulary,

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Göran Eckerwall, MSD
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=398&filename=CSR-D589GC00002.pdf
Download
CSR-D589GC00002.pdf
Download
D589GC00002 Clinical Study Protocol
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

Information.Center@AstraZeneca.com

Investigators

Principal Investigator

Lars-Goran Carlsson

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=398&filename=CSR-D589GC00002.pdf

CSR-D589GC00002.pdf

D589GC00002 Clinical Study Protocol

Trial Results Summaries