efficacy and tolerability of Symbicort as an add-on treatment to Spiriva compare with Spiriva alone in patients with severe chronic obstructive pulmonary disease (COPD) - SECURE 1

Study identifier:D589BL00023

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A randomised, parallel-group, open-label, multicentre, 3-month phase IV, efficacy and tolerability study of budesonide/formoterol (Symbicort® Turbuhaler® 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (SpirivaTM 18 μg/inhalation, 1 inhalation once daily) compared with tiotropium (SpirivaTM18 μg/inhalation, 1 inhalation once daily) alone in severe chronic obstructive pulmonary disease (COPD) patients

Medical condition

Chronic obstructive pulmonary disease (COPD)

Phase

Phase 4

Healthy volunteers

Study drug

Budesonide/formoterol (Symbicort® Turbuhaler®), Tiotropium (SpirivaTM)

Sex

All

Actual Enrollment

793

Study type

Interventional

Age

40 Years - 99 Years

Date

Study Start Date: 01 Jul 2011

Primary Completion Date: 01 Jun 2013

Study Completion Date: 01 Jun 2013

Study design

Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2015 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

GUANG ZHOU, China

Location

Research Site

BEIJING, Beijing, China

Location

Research Site

TAIYUAN, Shanxi, China

Location

Research Site

CHANGSHA, Hunan, China

Location

Research Site

SHANGHAI, Shanghai, China

Location

Research Site

SHEN YANG, Liaoning, China

Location

Research Site

CHANGCHUN, JILIN, China

Location

Research Site

GUANGZHOU, Guangdong, China

Arms	Assigned Interventions
Other: 1 Add-on treatment	Drug: Budesonide/formoterol (Symbicort® Turbuhaler®) Budesonide/formoterol (Symbicort® Turbuhaler®) 160/4.5μg/inhalation, 2 inhalations twice daily Drug: Tiotropium (SpirivaTM) Tiotropium (SpirivaTM) 18 μg/inhalation, 1 inhalation once daily
Other: 2 Add-on treatment	Drug: Tiotropium (SpirivaTM) Tiotropium (SpirivaTM) 18 μg/inhalation, 1 inhalation once daily

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There are 793 patients enrolled. 578 patients were randomized, where there are 287 patients randomized in Symbicort+ Spiriva group and 291 in Spiriva group

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
None

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Participant Flow: Overall Study

	Symbicort+Spiriva	Spiriva
STARTED	287	291
Post-baseline Efficacy Data Collected	287^[1]	290^[2]
Received Correct Randomized Treatment	286^[3]	287^[4]
COMPLETED	264	260
NOT COMPLETED	23	31
Withdrawal by Subject	7	11
Eligibility Criteria Not Fulfilled	7	6
Death	2	3
Lost to Follow-up	1	4
Condition under Investigation Worsened	1	3
Adverse Event	1	2
Severe Non-Compliance to Protocol	2	1
Others	2	1

[1]	'Full Analysis Set' used for efficacy analysis
[2]	'Full Analysis Set' used for efficacy analysis
[3]	'Safety Analysis Set' =287+3-1=289. 3 and 1 pts in respective groups received opposite treatment.
[4]	'Safety Analysis Set' =291+1-3=289.

Baseline Characteristics

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

Overall Number of Baseline Participants is not different from the Milestones.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Baseline Measures

	Symbicort+Spiriva	Spiriva	Total
Number of Participants [units: Participants]	287	290	577
Age Continuous [units: Years] Mean ± Standard Deviation	66.6 ± 7.99	66.9 ± 8.50	66.8 ± 8.25
Gender, Male/Female [units: Participants]
Female	8	17	25
Male	279	273	552

Outcome Measures

1. Primary Outcome Measure: Pre-dose FEV1 [ Time Frame: Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug ]

Measure Type	Primary
Measure Name	Pre-dose FEV1
Measure Description	Ratio of pre-dose FEV1 (Forced Expiratory Volume in 1 second) in treatment period to baseline value
Time Frame	Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	277
Pre-dose FEV1 [units: Ratio] Geometric Mean (95% Confidence Interval)	1.050 (1.030 to 1.070)	1.006 (0.987 to 1.025)

Statistical Analysis 1 for Pre-dose FEV1

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0004
Other^[5]	1.044
95% Confidence Interval	( 1.019 to 1.069 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	multiplicative ANCOVA model with treatment and country as fixed factors and baseline value as a (log-transformed) 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:
	No text entered.

2. Secondary Outcome Measure: Post-dose FEV1 at 5 Minutes [ Time Frame: Baseline (-2 weeks) and mean in treatment period (1, 6, 12 weeks) measured at 5 minutes after inhalation of study drug ]

Measure Type	Secondary
Measure Name	Post-dose FEV1 at 5 Minutes
Measure Description	Ratio of post-dose FEV1 at 5 minutes to baseline value
Time Frame	Baseline (-2 weeks) and mean in treatment period (1, 6, 12 weeks) measured at 5 minutes after inhalation of study drug
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	287	286
Post-dose FEV1 at 5 Minutes [units: Ratio] Geometric Mean (95% Confidence Interval)	1.128 (1.109 to 1.147)	1.045 (1.028 to 1.062)

Statistical Analysis 1 for Post-dose FEV1 at 5 Minutes

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	1.079
95% Confidence Interval	( 1.057 to 1.102 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

3. Secondary Outcome Measure: Post-dose FEV1 at 60 Minutes [ Time Frame: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12) ]

Measure Type	Secondary
Measure Name	Post-dose FEV1 at 60 Minutes
Measure Description	Ratio of post-dose FEV1 at 60 minutes to baseline value
Time Frame	Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	287	286
Post-dose FEV1 at 60 Minutes [units: Ratio] Geometric Mean (95% Confidence Interval)	1.164 (1.144 to 1.185)	1.072 (1.053 to 1.091)

Statistical Analysis 1 for Post-dose FEV1 at 60 Minutes

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	1.086
95% Confidence Interval	( 1.062 to 1.111 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

4. Secondary Outcome Measure: Pre-dose FVC [ Time Frame: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12) ]

Measure Type	Secondary
Measure Name	Pre-dose FVC
Measure Description	Ratio of pre-dose FVC (Forced Vital Capacity) in treatment period to baseline value
Time Frame	Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	277
Pre-dose FVC [units: Ratio] Geometric Mean (95% Confidence Interval)	1.032 (1.017 to 1.047)	1.013 (0.999 to 1.029)

Statistical Analysis 1 for Pre-dose FVC

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0570
Other^[5]	1.018
95% Confidence Interval	( 0.999 to 1.037 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

5. Secondary Outcome Measure: Post-dose FVC at 5 Minutes [ Time Frame: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 5 minutes after inhalation of study drug at weeks 0, 1, 6, 12) ]

Measure Type	Secondary
Measure Name	Post-dose FVC at 5 Minutes
Measure Description	Ratio of post-dose FVC at 5 minutes to baseline value
Time Frame	Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 5 minutes after inhalation of study drug at weeks 0, 1, 6, 12)
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	287	286
Post-dose FVC at 5 Minutes [units: Ratio] Geometric Mean (95% Confidence Interval)	1.096 (1.081 to 1.110)	1.044 (1.030 to 1.057)

Statistical Analysis 1 for Post-dose FVC at 5 Minutes

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	1.050
95% Confidence Interval	( 1.033 to 1.067 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

6. Secondary Outcome Measure: Post-dose FVC at 60 Minutes [ Time Frame: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12) ]

Measure Type	Secondary
Measure Name	Post-dose FVC at 60 Minutes
Measure Description	Ratio of post-dose FVC at 60 minutes to baseline value
Time Frame	Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	287	286
Post-dose FVC at 60 Minutes [units: Ratio] Geometric Mean (95% Confidence Interval)	1.116 (1.100 to 1.132)	1.059 (1.044 to 1.074)

Statistical Analysis 1 for Post-dose FVC at 60 Minutes

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	1.054
95% Confidence Interval	( 1.036 to 1.073 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

7. Secondary Outcome Measure: Pre-dose IC [ Time Frame: Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug ]

Measure Type	Secondary
Measure Name	Pre-dose IC
Measure Description	Ratio of pre-dose IC (Inspiratory Capacity) in treatment period to baseline value
Time Frame	Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	265	263
Pre-dose IC [units: Ratio] Geometric Mean (95% Confidence Interval)	1.042 (1.017 to 1.068)	1.022 (0.998 to 1.047)

Statistical Analysis 1 for Pre-dose IC

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.1956
Other^[5]	1.020
95% Confidence Interval	( 0.990 to 1.050 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

8. Secondary Outcome Measure: Post-dose IC at 60 Minutes [ Time Frame: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12) ]

Measure Type	Secondary
Measure Name	Post-dose IC at 60 Minutes
Measure Description	Ratio of post-dose IC at 60 minutes to baseline value
Time Frame	Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	263	270
Post-dose IC at 60 Minutes [units: Ratio] Geometric Mean (95% Confidence Interval)	1.154 (1.129 to 1.180)	1.087 (1.064 to 1.110)

Statistical Analysis 1 for Post-dose IC at 60 Minutes

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	1.062
95% Confidence Interval	( 1.035 to 1.091 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Multiplicative ANCOVA model with treatment and country as fixed factors and week 0 pre-dose value as a (log-transformed) 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:
	No text entered.

9. Secondary Outcome Measure: Pre-dose PEF in last week of treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the last week of treatment, up to 12 weeks ]

Measure Type	Secondary
Measure Name	Pre-dose PEF in last week of treatment
Measure Description	Change in pre-dose morning PEF (Peak Expiratory Flow) from run-in period to last week of treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the last week of treatment, up to 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	217	208
Pre-dose PEF in last week of treatment [units: L/min] Least Squares Mean (95% Confidence Interval)	15.753 (7.306 to 24.200)	-4.550 (-13.154 to 4.054)

Statistical Analysis 1 for Pre-dose PEF in last week of treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Mean Difference (Net)^[5]	20.303
95% Confidence Interval	( 9.904 to 30.702 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

10. Secondary Outcome Measure: Pre-dose PEF in first week of treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the first week of treatment ]

Measure Type	Secondary
Measure Name	Pre-dose PEF in first week of treatment
Measure Description	Change in pre-dose morning PEF (Peak Expiratory Flow) from run-in period to first week of treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the first week of treatment
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	239	241
Pre-dose PEF in first week of treatment [units: L/min] Least Squares Mean (95% Confidence Interval)	13.405 (8.464 to 18.345)	-0.182 (-4.994 to 4.630)

Statistical Analysis 1 for Pre-dose PEF in first week of treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	13.587
95% Confidence Interval	( 7.407 to 19.766 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

11. Secondary Outcome Measure: Pre-dose PEF in whole treatment period [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Pre-dose PEF in whole treatment period
Measure Description	Change in pre-dose morning PEF from run-in period to whole treatment period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	256	262
Pre-dose PEF in whole treatment period [units: L/min] Least Squares Mean (95% Confidence Interval)	12.271 (6.382 to 18.160)	-5.198 (-10.925 to 0.530)

Statistical Analysis 1 for Pre-dose PEF in whole treatment period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	17.469
95% Confidence Interval	( 10.147 to 24.791 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

12. Secondary Outcome Measure: Post-dose PEF in last week of treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the last week of treatment, up to 12 weeks ]

Measure Type	Secondary
Measure Name	Post-dose PEF in last week of treatment
Measure Description	Change in post-dose morning PEF at 5 minutes from run-period to last week of treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the last week of treatment, up to 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	177	162
Post-dose PEF in last week of treatment [units: L/min] Least Squares Mean (95% Confidence Interval)	23.379 (13.199 to 33.560)	-3.049 (-13.556 to 7.458)

Statistical Analysis 1 for Post-dose PEF in last week of treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Mean Difference (Net)^[5]	26.428
95% Confidence Interval	( 13.463 to 39.393 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

13. Secondary Outcome Measure: Post-dose PEF in first week of treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the first week of treatment ]

Measure Type	Secondary
Measure Name	Post-dose PEF in first week of treatment
Measure Description	Change in post-dose morning PEF at 5 minutes from run-in period to first week of treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the first week of treatment
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	186	201
Post-dose PEF in first week of treatment [units: L/min] Least Squares Mean (95% Confidence Interval)	17.412 (9.349 to 25.476)	0.220 (-7.486 to 7.926)

Statistical Analysis 1 for Post-dose PEF in first week of treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0006
Mean Difference (Net)^[5]	17.192
95% Confidence Interval	( 7.491 to 26.894 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

14. Secondary Outcome Measure: Post-dose PEF in whole treatment period [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Post-dose PEF in whole treatment period
Measure Description	Change in post-dose morning PEF at 5 minutes from run-period to whole treatment period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	248	247
Post-dose PEF in whole treatment period [units: L/min] Least Squares Mean (95% Confidence Interval)	15.880 (9.307 to 22.454)	-2.591 (-9.063 to 3.880)

Statistical Analysis 1 for Post-dose PEF in whole treatment period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	18.472
95% Confidence Interval	( 10.347 to 26.596 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

15. Secondary Outcome Measure: Use of reliever medication during day in the last week on treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 weeks ]

Measure Type	Secondary
Measure Name	Use of reliever medication during day in the last week on treatment
Measure Description	Change in the number of inhalations of reliever medication during day from run-in period to the last week on treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	274	274
Use of reliever medication during day in the last week on treatment [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.750 (-0.935 to 0.566)	-0.082 (-0.267 to 0.103)

Statistical Analysis 1 for Use of reliever medication during day in the last week on treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	-0.668
95% Confidence Interval	( -0.900 to -0.437 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

16. Secondary Outcome Measure: Use of reliever medication during day in the first week on treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the first week on treatment ]

Measure Type	Secondary
Measure Name	Use of reliever medication during day in the first week on treatment
Measure Description	Change in the number of inhalations of reliever medication during day from run-in period to the first week on treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the first week on treatment
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	284
Use of reliever medication during day in the first week on treatment [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.457 (-0.598 to -0.316)	-0.082 (-0.222 to 0.058)

Statistical Analysis 1 for Use of reliever medication during day in the first week on treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	-0.375
95% Confidence Interval	( -0.552 to -0.198 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

17. Secondary Outcome Measure: Use of reliever medication during day in the whole treatment period [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Use of reliever medication during day in the whole treatment period
Measure Description	Change in the number of inhalations of reliever medication during day from run-in period to the whole treatment period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	286
Use of reliever medication during day in the whole treatment period [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.685 (-0.836 to -0.533)	-0.134 (-0.284 to 0.016)

Statistical Analysis 1 for Use of reliever medication during day in the whole treatment period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	-0.551
95% Confidence Interval	( -0.741 to -0.361 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

18. Secondary Outcome Measure: Use of reliever medication during night in the last week on treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 weeks ]

Measure Type	Secondary
Measure Name	Use of reliever medication during night in the last week on treatment
Measure Description	Change in the number of inhalations of reliever medication during night from run-in period to the last week on treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	272	275
Use of reliever medication during night in the last week on treatment [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.174 (-0.299 to -0.049)	0.062 (-0.062 to 0.187)

Statistical Analysis 1 for Use of reliever medication during night in the last week on treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0028
Mean Difference (Net)^[5]	-0.236
95% Confidence Interval	( -0.391 to -0.082 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

19. Secondary Outcome Measure: Use of reliever medication during night in the first week on treatment [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during night in the first week on treatment ]

Measure Type	Secondary
Measure Name	Use of reliever medication during night in the first week on treatment
Measure Description	Change in the number of inhalations of reliever medication during day from run-in period to the first week on treatment
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during night in the first week on treatment
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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	283	286
Use of reliever medication during night in the first week on treatment [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.113 (-0.206 to -0.019)	0.011 (-0.081 to 0.104)

Statistical Analysis 1 for Use of reliever medication during night in the first week on treatment

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0372
Mean Difference (Net)^[5]	-0.124
95% Confidence Interval	( -0.240 to -0.007 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

20. Secondary Outcome Measure: Use of reliever medication during night in the whole treatment period [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Use of reliever medication during night in the whole treatment period
Measure Description	Change in the number of inhalations of reliever medication during night from run-in period to the whole treatment period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	285	286
Use of reliever medication during night in the whole treatment period [units: times/day] Least Squares Mean (95% Confidence Interval)	-0.241 (-0.336 to -0.147)	-0.010 (-0.104 to 0.084)

Statistical Analysis 1 for Use of reliever medication during night in the whole treatment period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Mean Difference (Net)^[5]	-0.231
95% Confidence Interval	( -0.350 to -0.113 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

21. Secondary Outcome Measure: Change in COPD symptoms - Breathing [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Change in COPD symptoms - Breathing
Measure Description	Change in breathing symptom score (from 0:none to 4:severe) from run-in period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	286
Change in COPD symptoms - Breathing [units: score on a scale] Least Squares Mean (95% Confidence Interval)	-0.372 (-0.454 to -0.290)	-0.110 (-0.191 to -0.029)

Statistical Analysis 1 for Change in COPD symptoms - Breathing

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	-0.262
95% Confidence Interval	( -0.364 to -0.159 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

22. Secondary Outcome Measure: Change in COPD symptoms - Cough [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Change in COPD symptoms - Cough
Measure Description	Change in Cough symptom score (from 0:none to 4:severe) from run-in period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	283	286
Change in COPD symptoms - Cough [units: score on a scale] Least Squares Mean (95% Confidence Interval)	-0.311 (-0.394 to -0.229)	-0.169 (-0.250 to -0.087)

Statistical Analysis 1 for Change in COPD symptoms - Cough

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0067
Mean Difference (Net)^[5]	-0.143
95% Confidence Interval	( -0.246 to -0.040 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

23. Secondary Outcome Measure: Change in COPD symptoms - Sputum [ Time Frame: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	Change in COPD symptoms - Sputum
Measure Description	Change in Sputum symptom score (from 0:none to 4:severe) from run-in period
Time Frame	Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	284	286
Change in COPD symptoms - Sputum [units: score on a scale] Least Squares Mean (95% Confidence Interval)	-0.216 (-0.295 to -0.136)	-0.094 (-0.173 to -0.014)

Statistical Analysis 1 for Change in COPD symptoms - Sputum

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0171
Mean Difference (Net)^[5]	-0.122
95% Confidence Interval	( -0.222 to -0.022 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Additive ANCOVA model with treatment and centre as fixed factors and the run-in mean of pre-dose morning PEF as a 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:
	No text entered.

24. Secondary Outcome Measure: COPD exacerbations [ Time Frame: Whole treatment period of 12 weeks ]

Measure Type	Secondary
Measure Name	COPD exacerbations
Measure Description	Severe exacerbations requiring systemic steroids (oral ≥3 days or parenteral) or hospitalisation or emergency room treatment due to worsening of COPD symptoms
Time Frame	Whole treatment period of 12 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.
FAS (287 + 290); less number of patients analyzed was caused by missing values.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Measured Values

	Symbicort+Spiriva	Spiriva
Number of Participants Analyzed [units:participants]	287	290
COPD exacerbations [units: exacerbations/participant/12 weeks] Least Squares Mean (95% Confidence Interval)	0.182 (0.138 to 0.239)	0.307 (0.248 to 0.379)

Statistical Analysis 1 for COPD exacerbations

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Poisson regression]
P-Value^[4]	0.0032
Other^[5]	0.593
95% Confidence Interval	( 0.419 to 0.839 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model with treatment as a factor and the duration time in study as an offset variable morning PEF as a 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:
	No text entered.

Statistical Analysis 2 for COPD exacerbations

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Regression, Cox
P-Value^[4]	0.0167
Cox Proportional Hazard^[5]	0.614
95% Confidence Interval	( 0.412 to 0.916 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Time to the first COPD exacerbation
[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 COPD exacerbations

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Log Rank
P-Value^[4]	0.0196

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[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.

Serious Adverse Events

Time Frame	12 weeks of treatment period
Additional Description	No text entered.

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Serious Adverse Events

Symbicort+Spiriva

Spiriva

Total, serious adverse events

# participants affected / at risk

14/289 (4.84%)

24/289 (8.30%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

7/289 (2.42%)

13/289 (4.50%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

2/289 (0.69%)

4/289 (1.38%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary oedema¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Infections and infestations

H1N1 influenza¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Metabolism and nutrition disorders

Hyperglycaemia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

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

Gastric cancer¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

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

Metastases to bone¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

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

Metastatic renal cell carcinoma¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Cardiac disorders

Supraventricular tachycardia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Cardiac disorders

Cardiac failure congestion¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Gastrointestinal disorders

Gastroenteritis¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

General disorders

Death¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Hepatobiliary disorders

Bile duct cancer¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Nervous system disorders

Presyncope¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Musculoskeletal and connective tissue disorders

Joint dislocation¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Spinal column stenosis¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 13.1

Other Adverse Events

Time Frame	12 weeks of treatment period
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Symbicort+Spiriva	Budesonide/formoterol (Symbicort Turbuhaler 160/4.5μg/inhalation, 2 inhalations twice daily) added to tiotropium (Spiriva 18 μg/inhalation, 1 inhalation once daily)
Spiriva	Spiriva 18 μg/inhalation, 1 inhalation once daily

Other Adverse Events

Symbicort+Spiriva

Spiriva

Total, other (not including serious) adverse events

# participants affected / at risk

75/289 (25.95%)

76/289 (26.30%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis¹,^†

# participants affected / at risk

6/289 (2.08%)

13/289 (4.50%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

2/289 (0.69%)

7/289 (2.42%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

2/289 (0.69%)

3/289 (1.04%)

# events

Respiratory, thoracic and mediastinal disorders

Pharyngitis¹,^†

# participants affected / at risk

2/289 (0.69%)

3/289 (1.04%)

# events

Respiratory, thoracic and mediastinal disorders

Rhinorrhoea¹,^†

# participants affected / at risk

1/289 (0.35%)

2/289 (0.69%)

# events

Respiratory, thoracic and mediastinal disorders

Rhonchi¹,^†

# participants affected / at risk

0/289 (0.00%)

2/289 (0.69%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchitis¹,^†

# participants affected / at risk

5/289 (1.73%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Haemoptysis¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

2/289 (0.69%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Sputum increased¹,^†

# participants affected / at risk

5/289 (1.73%)

1/289 (0.35%)

# events

Respiratory, thoracic and mediastinal disorders

Chest discomfort¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Chest pain¹,^†

# participants affected / at risk

2/289 (0.69%)

0/289 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dry throat¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dysphonia¹,^†

# participants affected / at risk

5/289 (1.73%)

0/289 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Productive cough¹,^†

# participants affected / at risk

2/289 (0.69%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

3/289 (1.04%)

4/289 (1.38%)

# events

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

2/289 (0.69%)

3/289 (1.04%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

1/289 (0.35%)

2/289 (0.69%)

# events

Gastrointestinal disorders

Gastritis¹,^†

# participants affected / at risk

1/289 (0.35%)

2/289 (0.69%)

# events

Gastrointestinal disorders

Abdominal discomfort¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Gastrointestinal disorders

Abdominal distension¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Gastrointestinal disorders

Dysphagia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Gastrointestinal disorders

Faecal incontinence¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Gastrointestinal disorders

Stomatitis¹,^†

# participants affected / at risk

1/289 (0.35%)

# events

Gastrointestinal disorders

Aphthous stomatitis¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Colon adenoma¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

2/289 (0.69%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Gastroenteritis¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Gastrointestinal disorders

Gingival oedema¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Infections and infestations

Oral candidiasis¹,^†

# participants affected / at risk

3/289 (1.04%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

5/289 (1.73%)

3/289 (1.04%)

# events

Infections and infestations

Herpes zoster¹,^†

# participants affected / at risk

0/289 (0.00%)

2/289 (0.69%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Infections and infestations

Candidiasis¹,^†

# participants affected / at risk

1/289 (0.35%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

4/289 (1.38%)

1/289 (0.35%)

# events

Infections and infestations

Pharyngitis¹,^†

# participants affected / at risk

1/289 (0.35%)

# events

Infections and infestations

Post herpetic neuralgia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/289 (0.35%)

4/289 (1.38%)

# events

Nervous system disorders

Dementia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

2/289 (0.69%)

1/289 (0.35%)

# events

Nervous system disorders

Lumbar radiculopathy¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Skin and subcutaneous tissue disorders

Dermatitis¹,^†

# participants affected / at risk

1/289 (0.35%)

3/289 (1.04%)

# events

Skin and subcutaneous tissue disorders

Rash¹,^†

# participants affected / at risk

0/289 (0.00%)

2/289 (0.69%)

# events

Skin and subcutaneous tissue disorders

Eczema¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

2/289 (0.69%)

1/289 (0.35%)

# events

Skin and subcutaneous tissue disorders

Skin irritation¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

General disorders

Chest pain¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

General disorders

Gait disturbance¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

General disorders

Oedema¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

General disorders

Oedema peripheral¹,^†

# participants affected / at risk

2/289 (0.69%)

1/289 (0.35%)

# events

General disorders

Pyrexia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

General disorders

Chills¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

General disorders

Influenza like illness¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

1/289 (0.35%)

2/289 (0.69%)

# events

Musculoskeletal and connective tissue disorders

Bursitis¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Musculoskeletal and connective tissue disorders

Joint swelling¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

6/289 (2.08%)

1/289 (0.35%)

# events

Musculoskeletal and connective tissue disorders

Spondylitis¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

2/289 (0.69%)

0/289 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Fracture¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Muscle spasms¹,^†

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Metabolism and nutrition disorders

Hypoalbuminaemia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Metabolism and nutrition disorders

Hypokalaemia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Hepatobiliary disorders

Hyperplastic cholecystopathy ¹

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Injury, poisoning and procedural complications

Open wound ¹

# participants affected / at risk

2/289 (0.69%)

1/289 (0.35%)

# events

Injury, poisoning and procedural complications

Muscle strain¹

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Investigations

Sputum abnormal¹

# participants affected / at risk

0/289 (0.00%)

1/289 (0.35%)

# events

Reproductive system and breast disorders

Benign prostatic hyperplasia ¹

# participants affected / at risk

1/289 (0.35%)

# events

Blood and lymphatic system disorders

Eosinophilia¹

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

Vascular disorders

Hypertension¹

# participants affected / at risk

1/289 (0.35%)

0/289 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 13.1

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: The PI Disclosure Restriction is indicated in the Clinical Study Agreement, please refer to this document of each PI and country.

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:	Nongluk Yimsuan
Organization:	AstraZeneca
Phone	66 2 7397400 Ext: 429
E-mail:	[email protected]

Documents available

CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

null AstraZeneca Clinical Study Information

0066 2 7397400

ClinicalTrialTransparency@astrazeneca.com

Investigators

Principal Investigator

Samuel Chen

AstraZeneca Pharmaceutical Co., Ltd., Shanghai, China

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site