A clinical study to evaluate Symbicort Turbuhaler used ’as needed’ in adults and adolescents with asthma - SYGMA2

Study identifier:D589SC00003

ClinicalTrials.gov identifier:NCT02224157

EudraCT identifier:2013-004473-28

CTIS identifier:N/A

Study Complete

Official Title

A Clinical Study Comparing Symbicort 'as Needed' With Pulmicort Twice Daily Plus Terbutaline 'as Needed' in Adult and Adolescent Patients With Asthma

Medical condition

asthma

Phase

Phase 3

Healthy volunteers

Study drug

budesonide/formoterol 'as needed' + budesonide placebo bid, budesonode bid + terbutaline 'as needed'

Sex

All

Actual Enrollment

4215

Study type

Interventional

Age

12 Years - 130 Years

Date

Study Start Date: 28 Nov 2014

Primary Completion Date: 16 Aug 2017

Study Completion Date: 16 Aug 2017

Study design

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

Verification:

Verified 01 Nov 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Sofia, Bulgaria, 1407

Location

Research Site

Sofia, Bulgaria

Location

Research Site

Varna, Bulgaria, 9000

Location

Research Site

Sofia, Bulgaria, 1431

Location

Research Site

Sofia, Bulgaria, 1408

Location

Research Site

Pernik, Bulgaria, 2300

Location

Research Site

Yambol, Bulgaria, 8600

Location

Research Site

Sliven, Bulgaria, 8800

Arms	Assigned Interventions
Experimental: Symbicort "as needed"+placebo Pulmicort bid Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid	Drug: budesonide/formoterol 'as needed' + budesonide placebo bid Symbicort (budesonide/ formoterol) 160/4.5 μg powder for inhalation 'as needed' plus Pulmicort placebo 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment
Active Comparator: Pulmicort bid + terbutaline "as needed" Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed'	Drug: budesonode bid + terbutaline 'as needed' Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening) plus terbutaline 0.4 mg powder for inhalation 'as needed', 52-week treatment

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
4215 patients were enrolled. 26 patients were randomised in error and hence never recieved treatment.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Screening Details Eligibility was assessed at Visits 1, 2 and 3. IC was obtained at V1. At V2, patients stopped pre-study asthma medications and entered a 2 to 4 week run-in period on SABA as needed only (Bricanyl Turbuhaler 0.5 mg). Lung function was assessed by spirometry to confirm eligibility. Eligible patients were randomised at V3.

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Participant Flow: Overall Study

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
STARTED	2095	2094
Patients who completed treatment	1924	1903
COMPLETED	1985	1983
NOT COMPLETED	110	111
Severe non-compliance to protocol	2	2
not specified	13	10
Subject decision	58	50
Prematurely closed site	4	2
Eligibility criteria not fulfilled	4	8
Lost to Follow-up	27	35
Death	1	1
Adverse Event	1	3

Baseline Characteristics

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

Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Baseline Measures

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Total
Number of Participants [units: Participants]	2089	2087	4176
Age Continuous [units: Years] Mean ± Standard Deviation	41.3 ± 16.8	40.7 ± 17.1	41.0 ± 17.0
Sex/Gender, Customized [units: Participants]
Female	1308	1289	2597
Male	781	798	1579
Race/Ethnicity, Customized [units: Participants]
American Indian or Alaska Native	36	32	68
Asian	399	403	802
Native Hawaiian or Other Pacific Islander	1	2	3
Black or African American	34	33	67
White	1408	1406	2814
Other	211	211	422

Outcome Measures

1. Primary Outcome Measure: Annual severe asthma exacerbation rate - Non-inferiority analysis [ Time Frame: up to 52 weeks ]

Measure Type	Primary
Measure Name	Annual severe asthma exacerbation rate - Non-inferiority analysis
Measure Description	Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation
Time Frame	up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Annual severe asthma exacerbation rate - Non-inferiority analysis [units: exacerbations per participant year] Least Squares Mean (95% Confidence Interval)	0.11 (0.10 to 0.13)	0.12 (0.10 to 0.14)

Statistical Analysis 1 for Annual severe asthma exacerbation rate - Non-inferiority analysis

Groups^[1]	All groups
Method^[3]	Other [Negative binomial model]
Other^[5]	0.97
95% Confidence Interval	( --- to 1.16 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Adjusted for randomised treatment, pre-study treatment and region. Logarithm of follow-up time is used as an offset variable.
[5]	Other relevant estimation information:
	A rate ratio less than 1 indicates a lower rate of exacerbations in the Symbicort 'as needed' treatment group.

2. Primary Outcome Measure: Annual severe asthma exacerbation rate - Superiority analysis [ Time Frame: up to 52 weeks ]

Measure Type	Primary
Measure Name	Annual severe asthma exacerbation rate - Superiority analysis
Measure Description	Severe asthma exacerbations over the randomised treatment period, negative binomial model for superiority test evaluation
Time Frame	up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Annual severe asthma exacerbation rate - Superiority analysis [units: exacerbations per participant year] Least Squares Mean (95% Confidence Interval)	0.11 (0.10 to 0.13)	0.12 (0.10 to 0.14)

Statistical Analysis 1 for Annual severe asthma exacerbation rate - Superiority analysis

Groups^[1]	All groups
Method^[3]	Other [Negative binomial model]
P-Value^[4]	0.754
Other^[5]	0.97
95% Confidence Interval	( 0.78 to 1.20 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Adjusted for randomised treatment, pre-study treatment and region. Logarithm of follow-up time is used as an offset variable.
[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:
	A rate ratio less than 1 indicates a lower rate of exacerbations in the Symbicort 'as needed' treatment group.

3. Secondary Outcome Measure: Number of participants experiencing at least one severe asthma exacerbation [ Time Frame: Day 1 up to 52 weeks ]

Measure Type	Secondary
Measure Name	Number of participants experiencing at least one severe asthma exacerbation
Measure Description	A severe exacerbation is defined as a deterioration of asthma requiring any of the following: use of systemic glucocorticosteroids (GCS) for at least 3 days, inpatient hospitalization, or emergency room visit due to asthma that required systemic steroids.
Time Frame	Day 1 up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Number of participants experiencing at least one severe asthma exacerbation [units: Participants]	177	184

Statistical Analysis 1 for Number of participants experiencing at least one severe asthma exacerbation

Groups^[1]	All groups
Method^[3]	Regression, Cox
P-Value^[4]	0.664
Hazard Ratio (HR)^[5]	0.955
95% Confidence Interval	( 0.777 to 1.174 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Cox regression model with randomised treatment, pre-study treatment and region as covariates.
[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:
	A hazard ratio less than 1 indicates that Symbicort 'as needed' prolongs the time to first severe exacerbation.

4. Secondary Outcome Measure: Average change from baseline in pre-bronchodilator FEV1 [ Time Frame: Study weeks 0,17, 34, 52 ]

Measure Type	Secondary
Measure Name	Average change from baseline in pre-bronchodilator FEV1
Measure Description	The average change from baseline (baseline defined by measurement at week 0, prior to first dose of IP) to the treatment period average assessed over the entire treatment period in pre-bronchodilator FEV1 was derived by computing a contrast for the mean across the post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.
Time Frame	Study weeks 0,17, 34, 52
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Average change from baseline in pre-bronchodilator FEV1 [units: mL] Least Squares Mean (95% Confidence Interval)	104.0 (88.5 to 119.6)	136.6 (121.1 to 152.2)

Statistical Analysis 1 for Average change from baseline in pre-bronchodilator FEV1

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.003
Other^[5]	-32.6
95% Confidence Interval	( -53.7 to -11.4 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Rand treatment,pre-study treatment,region,visit,rand treatment by visit; fixed effects. Patient; random effect, baseline FEV1; covariate.
[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:
	Mean difference greater than 0 favours Symbicort 'as needed'. Estimate corresponds to average treatment effect across all treatment visits.

5. Secondary Outcome Measure: Number of participants with study specific asthma related discontinuation [ Time Frame: Day 1 up to 52 weeks ]

Measure Type	Secondary
Measure Name	Number of participants with study specific asthma related discontinuation
Measure Description	The following two criteria lead to discontinuation from the IP due to asthma related events: A severe asthma exacerbation with duration for more than 3 weeks, and/or three severe asthma exacerbations during 6 months.
Time Frame	Day 1 up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Number of participants with study specific asthma related discontinuation [units: Participants]	0	4

No statistical analysis provided for Number of participants with study specific asthma related discontinuation

6. Secondary Outcome Measure: Average change from baseline in ‘as needed’ use [ Time Frame: Week 0 up to 52 weeks ]

Measure Type	Secondary
Measure Name	Average change from baseline in ‘as needed’ use
Measure Description	‘As-needed’ use change from baseline over the randomised treatment period. Baseline was defined as the last 10 days of the run-in period. 'As needed' use was calculated as the cumulative doses of ‘as-needed’ medication over the randomised treatment period divided by the follow-up time (number of days - 1). ie, average number of inhalations per day.
Time Frame	Week 0 up to 52 weeks
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.
Full analysis set.

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Average change from baseline in ‘as needed’ use [units: Number of inhalations per day] Least Squares Mean (95% Confidence Interval)	-0.84 (-0.86 to -0.81)	-0.87 (-0.89 to -0.84)

Statistical Analysis 1 for Average change from baseline in ‘as needed’ use

Groups^[1]	All groups
Method^[3]	ANCOVA
Other^[5]	0.03
95% Confidence Interval	( 0.00 to 0.07 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model with randomised treatment, pre-study treatment and region as factors, and no. of 'as needed' inhalations at baseline as continuous covariate
[5]	Other relevant estimation information:
	A mean difference less than zero indicates a larger mean reduction in number of 'as needed' inhalations in the Symbicort 'as needed' group.

7. Secondary Outcome Measure: Change from baseline in percent of ‘as needed’ free days [ Time Frame: Week 0 up to 52 weeks ]

Measure Type	Secondary
Measure Name	Change from baseline in percent of ‘as needed’ free days
Measure Description	‘As needed’ free days (%) change from baseline during randomised treatment period. An 'as-needed' free day was defined as a day and night with no use of 'as needed' medication. Variable analysed is the percentage (%) of 'as-needed' free days during the randomised treatment period. Baseline is defined by the last 10 days of the run-in period.
Time Frame	Week 0 up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Change from baseline in percent of ‘as needed’ free days [units: Percentage of 'as needed' free days] Least Squares Mean (95% Confidence Interval)	41.01 (39.90 to 42.12)	47.86 (46.75 to 48.98)

Statistical Analysis 1 for Change from baseline in percent of ‘as needed’ free days

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	< 0.001
Other^[5]	-6.85
95% Confidence Interval	( -8.37 to -5.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	adjusted for randomised treatment, pre-study treatment and region as factors and the percent 'as needed' free days during run-in as a cont covariate.
[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:
	An estimate of difference >0 means that there was a larger increase in the % of 'as needed' free days in the Symbicort 'as-needed' arm.

8. Secondary Outcome Measure: Percentage of controller use days [ Time Frame: Week 0 up to 52 weeks ]

Measure Type	Secondary
Measure Name	Percentage of controller use days
Measure Description	ICS controller use days (%) during the randomised treatment period is calculated as the cumulative days when any controller medication (containing ICS) was taken including maintenance (Pulmicort bid group) and 'as needed' medication (Symbicort 'as needed' group) and additional prescribed ICS for asthma (all treatment groups), divided by the number of days in the randomised treatment period.
Time Frame	Week 0 up to 52 weeks
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.
Full analysis set

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Percentage of controller use days [units: Percentage of days] Least Squares Mean (95% Confidence Interval)	30.45 (29.20 to 31.70)	67.92 (66.67 to 69.17)

Statistical Analysis 1 for Percentage of controller use days

Groups^[1]	All groups
Method^[3]	ANOVA
P-Value^[4]	<0.001
Other^[5]	-37.48
95% Confidence Interval	( -39.18 to -35.77 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	model adjusted for: randomised treatment, pre-study treatment and region.
[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:
	An estimate of difference >0 means that there was a higher % of controller use days in the Symbicort 'as-needed' group.

9. Secondary Outcome Measure: Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score [ Time Frame: Study weeks 0, 17, 34, 52 ]

Measure Type	Secondary
Measure Name	Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score
Measure Description	ACQ questionnaire contains five questions on patients' symptoms, which are assessed on a 7-point scale from 0 (representing good control) to 6 (representing poor control). The score is the mean score of all questions for which responses are provided. The average change from baseline to treatment period average in ACQ-5 was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.
Time Frame	Study weeks 0, 17, 34, 52
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.
Full analysis set.

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score [units: Score] Least Squares Mean (95% Confidence Interval)	-0.35 (-0.38 to -0.32)	-0.46 (-0.49 to -0.43)

Statistical Analysis 1 for Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	0.109
95% Confidence Interval	( 0.068 to 0.150 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	rand treatment, pre-study treatment, region, visit, rand treat by visit as fixed, patient as random, and baseline ACQ-5 as covariate.
[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:
	Mean difference less than 0 favours Symbicort 'as needed'.

10. Secondary Outcome Measure: Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score [ Time Frame: Study weeks 0,17, 34, 52 ]

Measure Type	Secondary
Measure Name	Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score
Measure Description	AQLQ(S) consists of 32 questions in 4 domains. Each question is assessed on a 7-point scale from 1 to 7, with higher values indicating better health-related quality of life. The overall score is calculated as the mean score of all 32 items. The average change from baseline to treatment period average in AQLQ(S) overall score was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.
Time Frame	Study weeks 0,17, 34, 52
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.
Full Analysis Set.

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Measured Values

	Placebo bid + Symbicort 'as needed' (Experimental)	Pulmicort bid + terbutaline 'as needed' (Active Comparator)
Number of Participants Analyzed [units:participants]	2089	2087
Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score [units: AQLQ(S) overall score] Least Squares Mean (95% Confidence Interval)	0.335 (0.305 to 0.366)	0.431 (0.400 to 0.461)

Statistical Analysis 1 for Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.096
95% Confidence Interval	( -0.137 to -0.054 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	rand treatment, pre-study treatment, region, visit, rand treat by visit as fixed, patient as random and baseline AQLQ as covariate.
[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:
	Mean difference greater than 0 favours Symbicort 'as needed'.

Serious Adverse Events

Time Frame	Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Additional Description	No text entered.

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Serious Adverse Events

Placebo bid + Symbicort 'as needed' (Experimental)

Pulmicort bid + terbutaline 'as needed' (Active Comparator)

Total, serious adverse events

# participants affected / at risk

66/2089 (3.16%)

73/2087 (3.50%)

Infections and infestations

Acute sinusitis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

2/2089 (0.10%)

1/2087 (0.05%)

# events

Infections and infestations

Chronic sinusitis¹,^†

# participants affected / at risk

2/2089 (0.10%)

0/2087 (0.00%)

# events

Infections and infestations

Cystitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Dengue fever¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Infections and infestations

Pharyngitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

2/2089 (0.10%)

1/2087 (0.05%)

# events

Infections and infestations

Pneumonia bacterial¹,^†

# participants affected / at risk

1/2089 (0.05%)

2/2087 (0.10%)

# events

Infections and infestations

Pneumonia pneumococcal¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Postoperative wound infection¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Pyelonephritis acute¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Infections and infestations

Urinary tract infection bacterial¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Infections and infestations

Vestibular neuronitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Benign neoplasm of skin¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Breast cancer female¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Cervix carcinoma¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Fibroadenoma of breast¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Sebaceous adenoma¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Seborrhoeic keratosis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uterine leiomyoma¹,^†

# participants affected / at risk

0/2089 (0.00%)

2/2087 (0.10%)

# events

Immune system disorders

Anaphylactic reaction¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Immune system disorders

Drug hypersensitivity¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Metabolism and nutrition disorders

Diabetes mellitus inadequate control¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Nervous system disorders

Carpal tunnel syndrome¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Nervous system disorders

Epilepsy¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Nervous system disorders

Lumbar radiculopathy¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Nervous system disorders

Radiculopathy¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Eye disorders

Cataract¹,^†

# participants affected / at risk

2/2089 (0.10%)

0/2087 (0.00%)

# events

Eye disorders

Visual impairment¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Ear and labyrinth disorders

Deafness neurosensory¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Cardiac disorders

Adams-Stokes syndrome¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Cardiac disorders

Atrial fibrilation¹,^†

# participants affected / at risk

0/2089 (0.00%)

2/2087 (0.10%)

# events

Cardiac disorders

Atrioventricular block complete¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Cardiac disorders

Cardio-respiratory arrest¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Cardiac disorders

Cardiomyopathy¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Cardiac disorders

Degenerative aortic valve disease¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

2/2089 (0.10%)

0/2087 (0.00%)

# events

Vascular disorders

Hypertensive crisis¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Vascular disorders

Peripheral arterial occlusive disease¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Vascular disorders

Thrombophlebitis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

17/2089 (0.81%)

17/2087 (0.81%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal polyps¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal turbinate hypertrophy¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Vocal cord polyp¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Hepatobiliary disorders

Biliary colic¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Hepatobiliary disorders

Cholecystitis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Hepatobiliary disorders

Hydrocholecystitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Hepatobiliary disorders

Sphincter of Oddi dysfunction¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Skin and subcutaneous tissue disorders

Angioedema¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Skin and subcutaneous tissue disorders

Hirsutism¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Intervertebral disc protusion¹,^†

# participants affected / at risk

0/2089 (0.00%)

2/2087 (0.10%)

# events

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

1/2089 (0.05%)

2/2087 (0.10%)

# events

Musculoskeletal and connective tissue disorders

Rotator cuff syndrome¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Spinal osteoarthritis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Gastrointestinal disorders

Haemorrhoidal haemorrhage¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Gastrointestinal disorders

Incarcerated umbilical hernia¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Gastrointestinal disorders

Inguinal hernia¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Renal and urinary disorders

Cystistis interstitial¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Renal and urinary disorders

Ureteric stenosis¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Reproductive system and breast disorders

Adenomyosis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Reproductive system and breast disorders

Breast mass¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Reproductive system and breast disorders

Endometrial hyperplasia¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Reproductive system and breast disorders

Endometriosis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Reproductive system and breast disorders

Menorrhagia¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Reproductive system and breast disorders

Prostatitis¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Reproductive system and breast disorders

Rectocele¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Reproductive system and breast disorders

Uterine polyp¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Abdominal injury¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Arthropod bite¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Fracture¹,^†

# participants affected / at risk

0/2089 (0.00%)

2/2087 (0.10%)

# events

Injury, poisoning and procedural complications

Hand fracture¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Head injury¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Humerus fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Ligament injury¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Limb injury¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Lower limb fracture¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Lumbosacral plexus injury¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Post procedural swelling¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Radius fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Road traffic accident¹,^†

# participants affected / at risk

1/2089 (0.05%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Subarachnoid haemorrhage¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Subdural haematoma¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Tendon rupture¹,^†

# participants affected / at risk

0/2089 (0.00%)

1/2087 (0.05%)

# events

Injury, poisoning and procedural complications

Upper limb fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

Injury, poisoning and procedural complications

Wrist fracture¹,^†

# participants affected / at risk

1/2089 (0.05%)

0/2087 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.0

Other Adverse Events

Time Frame	Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	2%

Reporting Groups

	Description
Placebo bid + Symbicort 'as needed' (Experimental)	Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
Pulmicort bid + terbutaline 'as needed' (Active Comparator)	Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

Other Adverse Events

Placebo bid + Symbicort 'as needed' (Experimental)

Pulmicort bid + terbutaline 'as needed' (Active Comparator)

Total, other (not including serious) adverse events

# participants affected / at risk

491/2089 (23.50%)

519/2087 (24.87%)

Infections and infestations

Viral upper respiratory tract infection¹,^†

# participants affected / at risk

155/2089 (7.42%)

168/2087 (8.05%)

# events

188

206

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

81/2089 (3.88%)

84/2087 (4.02%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

51/2089 (2.44%)

50/2087 (2.40%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

64/2089 (3.06%)

78/2087 (3.74%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

81/2089 (3.88%)

89/2087 (4.26%)

# events

112

Infections and infestations

Pharyngitis¹,^†

# participants affected / at risk

51/2089 (2.44%)

62/2087 (2.97%)

# events

Respiratory, thoracic and mediastinal disorders

Rhinitis allergic¹,^†

# participants affected / at risk

51/2089 (2.44%)

44/2087 (2.11%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

33/2089 (1.58%)

42/2087 (2.01%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.0

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.

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
No text entered.

Results Point of Contact

Name/Title:	Stefan Ivanov
Organization:	AstraZeneca AB
Phone	000000000
E-mail:	[email protected]

Documents available

D589SC00003-revised-csp-edition-4_12Oct2016_Redacted_pdfa
Download
D589SC00003-statistical-analysis-plan-edition-2_06SEP2017_pdfa
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Carin Jorup

AstraZeneca Research & Development

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

D589SC00003-revised-csp-edition-4_12Oct2016_Redacted_pdfa

D589SC00003-statistical-analysis-plan-edition-2_06SEP2017_pdfa

Trial Results Summaries