Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.

This study has been completed.

Sponsor:

Collaborator:

Pfizer

Information provided by:

Boehringer Ingelheim Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT00563381

First received: November 22, 2007

Last updated: July 10, 2012

Last verified: July 2012

History of Changes

Results First Received: March 29, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double-Blind; Primary Purpose: Treatment
Condition:	Pulmonary Disease, Chronic Obstructive
Interventions:	Drug: Tiotropium bromide Drug: Salmeterol Drug: Placebo Salmeterol Drug: Placebo Tiotropium

Participant Flow

Hide Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There were 8 patients (4:4 on Tiotropium and Salmeterol respectively) randomized but not treated

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Participant Flow: Overall Study

	Tiotropium	Salmeterol
STARTED	3707 ^[1]	3669 ^[1]
COMPLETED	3122 ^[2]	3021 ^[2]
NOT COMPLETED	585	648
Adverse Event	264	292
Protocol Violation	66	74
Lost to Follow-up	7	15
Withdrawal by Subject	192	209
Lack of Efficacy	32	24
Individual different reasons	24	34

[1]	Started treatment
[2]	Completed treatment

Baseline Characteristics

Hide Baseline Characteristics

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily
Total	Total of all reporting groups

Baseline Measures

	Tiotropium	Salmeterol	Total
Number of Participants [units: participants]	3707	3669	7376
Age [units: Years] Mean ± Standard Deviation	62.9 ± 9.0	62.8 ± 9.0	62.9 ± 9.0
Gender [units: Participants]
Female	948	922	1870
Male	2759	2747	5506
Race/Ethnicity, Customized [units: Participants]
Asian	5	3	8
Black	9	9	18
White	3693	3657	7350

Outcome Measures

Hide All Outcome Measures

1. Primary:

First Occurrence of (Moderate or Severe) COPD Exacerbation [ Time Frame: 52 weeks ]

Measure Type	Primary
Measure Title	First Occurrence of (Moderate or Severe) COPD Exacerbation
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of (Moderate or Severe) COPD Exacerbation [units: number of first occurrences]	1277	1414

Statistical Analysis 1 for First Occurrence of (Moderate or Severe) COPD Exacerbation

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.83
95% Confidence Interval	( 0.77 to 0.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

COPD Exacerbations Per Patient-year Leading to Hospitalisation [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	COPD Exacerbations Per Patient-year Leading to Hospitalisation
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
COPD Exacerbations Per Patient-year Leading to Hospitalisation [units: Hospitalizations per patient-year] Mean ( 95% Confidence Interval )	0.09 ( 0.09 to 0.10 )	0.13 ( 0.12 to 0.14 )

Statistical Analysis 1 for COPD Exacerbations Per Patient-year Leading to Hospitalisation

Groups ^[1]	All groups
Method ^[2]	Poisson regression
P Value ^[3]	<0.0001
Rate ratio (ratio of incidence rates) ^[4]	0.73
Standard Error of the mean	± 0.04
95% Confidence Interval	( 0.66 to 0.82 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium vs. Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression correcting for overdisperion and adjusted for treatment exposure
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

3. Secondary:

Number of Participants With at Least One COPD Exacerbation [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	Number of Participants With at Least One COPD Exacerbation
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
Number of Participants With at Least One COPD Exacerbation [units: Participants]
Participants with (at least one) event	1277	1414
Participants with no event	2430	2255

Statistical Analysis 1 for Number of Participants With at Least One COPD Exacerbation

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.0002
Risk Ratio (RR) ^[4]	0.90
95% Confidence Interval	( 0.85 to 0.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

4. Secondary:

COPD Exacerbations Per Patient-year [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	COPD Exacerbations Per Patient-year
Measure Description	No text entered.
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
COPD Exacerbations Per Patient-year [units: exacerbations per patient-year] Mean ( 95% Confidence Interval )	0.64 ( 0.61 to 0.67 )	0.72 ( 0.68 to 0.75 )

Statistical Analysis 1 for COPD Exacerbations Per Patient-year

Groups ^[1]	All groups
Method ^[2]	Poisson regression
P Value ^[3]	0.0017
Rate ratio (ratio of incidence rates) ^[4]	0.89
Standard Error of the mean	± 0.03
95% Confidence Interval	( 0.83 to 0.96 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression correcting for overdisperion and adjusted for treatment exposure
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

5. Secondary:

First Occurrence of COPD Exacerbation Leading to Hospitalization [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	First Occurrence of COPD Exacerbation Leading to Hospitalization
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation leading to hospitalisation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of COPD Exacerbation Leading to Hospitalization [units: number of first occurrences]	262	336

Statistical Analysis 1 for First Occurrence of COPD Exacerbation Leading to Hospitalization

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.72
95% Confidence Interval	( 0.61 to 0.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

6. Secondary:

Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation [units: Participants]
Participants with (at least one) event	262	336
Participants with no event	3445	3333

Statistical Analysis 1 for Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.0005
Risk Ratio (RR) ^[4]	0.77
95% Confidence Interval	( 0.66 to 0.89 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

7. Secondary:

Occurrence of Premature Discontinuation of Trial Medication [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	Occurrence of Premature Discontinuation of Trial Medication
Measure Description	Occurrence analysed by Cox regression as time to premature discontinuation of trial medication and reported as hazard ratio
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
Occurrence of Premature Discontinuation of Trial Medication [units: number of first occurrences]	585	648

Statistical Analysis 1 for Occurrence of Premature Discontinuation of Trial Medication

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	0.0242
Hazard Ratio (HR) ^[4]	0.88
95% Confidence Interval	( 0.78 to 0.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

8. Secondary:

Number of Participants With Premature Discontinuation of Trial Medication [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	Number of Participants With Premature Discontinuation of Trial Medication
Measure Description	No text entered.
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
Number of Participants With Premature Discontinuation of Trial Medication [units: Participants]
Participants with (at least one) event	585	648
Participants with no event	3122	3021

Statistical Analysis 1 for Number of Participants With Premature Discontinuation of Trial Medication

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.0406
Risk Ratio (RR) ^[4]	0.90
95% Confidence Interval	( 0.82 to 1.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

9. Secondary:

First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation or discontinuation of trial medication because of worsening of underlying disease, whichever comes first and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First [units: number of first occurrences]	1316	1448

Statistical Analysis 1 for First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.84
95% Confidence Interval	( 0.78 to 0.91 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

10. Secondary:

First Occurrence of COPD Exacerbations Treated With Systemic Steroids [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	First Occurrence of COPD Exacerbations Treated With Systemic Steroids
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of COPD Exacerbations Treated With Systemic Steroids [units: number of first occurrences]	715	852

Statistical Analysis 1 for First Occurrence of COPD Exacerbations Treated With Systemic Steroids

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.77
95% Confidence Interval	( 0.69 to 0.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

11. Secondary:

First Occurrence of COPD Exacerbations Treated With Antibiotics [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	First Occurrence of COPD Exacerbations Treated With Antibiotics
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation treated with antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of COPD Exacerbations Treated With Antibiotics [units: number of first occurrences]	1154	1259

Statistical Analysis 1 for First Occurrence of COPD Exacerbations Treated With Antibiotics

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.85
95% Confidence Interval	( 0.78 to 0.92 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

12. Secondary:

First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics
Measure Description	First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics [units: number of first occurrences]	562	671

Statistical Analysis 1 for First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.76
95% Confidence Interval	( 0.68 to 0.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment effect adjusted for pooled centre
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

13. Secondary:

COPD Exacerbations Treated With Systemic Steroids Per Patient-year [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	COPD Exacerbations Treated With Systemic Steroids Per Patient-year
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
COPD Exacerbations Treated With Systemic Steroids Per Patient-year [units: exacerbations per patient-year] Mean ( 95% Confidence Interval )	0.33 ( 0.31 to 0.36 )	0.41 ( 0.38 to 0.43 )

Statistical Analysis 1 for COPD Exacerbations Treated With Systemic Steroids Per Patient-year

Groups ^[1]	All groups
Method ^[2]	Poisson regression
P Value ^[3]	<0.0001
Rate ratio (ratio of incidence rates) ^[4]	0.82
Standard Error of the mean	± 0.04
95% Confidence Interval	( 0.76 to 0.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression correcting for overdispersion and adjusted for treatment exposure
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

14. Secondary:

COPD Exacerbations Treated With Antibiotics Per Patient-year [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	COPD Exacerbations Treated With Antibiotics Per Patient-year
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
COPD Exacerbations Treated With Antibiotics Per Patient-year [units: exacerbations per patient-year] Mean ( 95% Confidence Interval )	0.53 ( 0.50 to 0.56 )	0.59 ( 0.56 to 0.62 )

Statistical Analysis 1 for COPD Exacerbations Treated With Antibiotics Per Patient-year

Groups ^[1]	All groups
Method ^[2]	Poisson regression
P Value ^[3]	0.0036
Rate ratio (ratio of incidence rates) ^[4]	0.90
Standard Error of the mean	± 0.03
95% Confidence Interval	( 0.84 to 0.97 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression correcting for overdisperion and adjusted for treatment exposure
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

15. Secondary:

COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Title	COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year
Measure Description	An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Time Frame	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.
All patients who received study medication, were randomised, and were documented to have taken at least one dose of double-blind treatment

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	3707	3669
COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year [units: exacerbations per patient-year] Mean ( 95% Confidence Interval )	0.23 ( 0.21 to 0.24 )	0.28 ( 0.27 to 0.30 )

Statistical Analysis 1 for COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year

Groups ^[1]	All groups
Method ^[2]	Poisson regression
P Value ^[3]	<0.0001
Rate ratio (ratio of incidence rates) ^[4]	0.80
Standard Error of the mean	± 0.04
95% Confidence Interval	( 0.73 to 0.88 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression correcting for overdisperion and adjusted for treatment exposure
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

16. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2446	2434
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1 [units: liter per minute (L/min)] Mean ± Standard Error	222.85 ± 0.81	224.45 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.1035
difference in peak expiratory flow rates ^[4]	-1.60
95% Confidence Interval	( -3.53 to 0.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Mixed effects repeated measures model (MMRM) (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

17. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2413	2377
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2 [units: liter per minute (L/min)] Mean ± Standard Error	225.15 ± 0.81	227.21 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.0369
difference in peak expiratory flow rates ^[4]	-2.06
95% Confidence Interval	( -3.99 to -0.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Mixed effects repeated measures model (MRMM)(fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek).
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

18. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2394	2357
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3 [units: liter per minute (L/min)] Mean ± Standard Error	226.31 ± 0.81	228.38 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.0362
difference in peak expiratory flow rates ^[4]	-2.07
95% Confidence Interval	( -4.00 to -0.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

19. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2380	2349
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4 [units: liter per minute (L/min)] Mean ± Standard Error	227.37 ± 0.81	229.25 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.0573
difference in peak expiratory flow rates ^[4]	-1.88
95% Confidence Interval	( -3.82 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

20. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2360	2335
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5 [units: liter per minute (L/min)] Mean ± Standard Error	228.27 ± 0.81	229.37 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.2641
difference in peak expiratory flow rates ^[4]	-1.10
95% Confidence Interval	( -3.04 to 0.83 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

21. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2351	2319
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6 [units: liter per minute (L/min)] Mean ± Standard Error	228.80 ± 0.82	229.81 ± 0.81

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.3068
difference in peak expiratory flow rates ^[4]	-1.01
95% Confidence Interval	( -2.95 to 0.93 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

22. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2339	2306
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7 [units: liter per minute (L/min)] Mean ± Standard Error	229.35 ± 0.82	230.13 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.4299
difference in peak expiratory flow rates ^[4]	-0.78
95% Confidence Interval	( -2.72 to 1.16 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

23. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2319	2278
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8 [units: liter per minute (L/min)] Mean ± Standard Error	229.95 ± 0.82	230.43 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.6277
difference in peak expiratory flow rates ^[4]	-0.48
95% Confidence Interval	( -2.42 to 1.46 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

24. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2279	2234
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9 [units: liter per minute (L/min)] Mean ± Standard Error	229.72 ± 0.82	230.57 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.3931
difference in peak expiratory flow rates ^[4]	-0.85
95% Confidence Interval	( -2.80 to 1.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

25. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2285	2235
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10 [units: liter per minute (L/min)] Mean ± Standard Error	230.30 ± 0.82	231.27 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.3297
difference in peak expiratory flow rates ^[4]	-0.97
95% Confidence Interval	( -2.92 to 0.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

26. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2289	2228
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11 [units: liter per minute (L/min)] Mean ± Standard Error	230.61 ± 0.82	231.91 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.1904
difference in peak expiratory flow rates ^[4]	-1.30
95% Confidence Interval	( -3.25 to 0.65 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

27. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2286	2214
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12 [units: liter per minute (L/min)] Mean ± Standard Error	231.04 ± 0.82	232.04 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.3172
difference in peak expiratory flow rates ^[4]	-0.99
95% Confidence Interval	( -2.94 to 0.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

28. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2278	2212
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13 [units: liter per minute (L/min)] Mean ± Standard Error	231.23 ± 0.82	231.89 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.5017
difference in peak expiratory flow rates ^[4]	-0.67
95% Confidence Interval	( -2.62 to 1.28 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

29. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2264	2211
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14 [units: liter per minute (L/min)] Mean ± Standard Error	231.19 ± 0.82	232.42 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.2174
difference in peak expiratory flow rates ^[4]	-1.23
95% Confidence Interval	( -3.18 to 0.72 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

30. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2256	2193
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15 [units: liter per minute (L/min)] Mean ± Standard Error	231.64 ± 0.82	232.75 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.2682
difference in peak expiratory flow rates ^[4]	-1.10
95% Confidence Interval	( -3.05 to 0.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

31. Secondary:

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16 [ Time Frame: 16 weeks ]

Measure Type	Secondary
Measure Title	Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16
Measure Description	PEFR means peak expiratory flow rate and is measured in liter per minute
Time Frame	16 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.
All patients who received study medication, were randomised, were documented to have taken at least one dose of double-blind treatment, gave informed consent to genotyping, took part in the pre-specified part of the genotyping analysis, and who have evaluable blood samples

Reporting Groups

	Description
Tiotropium	Tiotropium 18 mcg once daily (QD) inhalation (powder) via HandiHaler® and matching Placebo metered dose inhaler (MDI) twice daily (BID)
Salmeterol	Salmeterol 50 mcg (2 actuations of 25 mcg) twice daily inhalation (suspension) via MDI and Placebo HandiHaler® once daily

Measured Values

	Tiotropium	Salmeterol
Number of Participants Analyzed [units: participants]	2240	2174
Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16 [units: liter per minute (L/min)] Mean ± Standard Error	232.06 ± 0.82	232.65 ± 0.82

Statistical Analysis 1 for Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16

Groups ^[1]	All groups
Method ^[2]	Mixed Effects Repeated Measures Model
P Value ^[3]	0.5520
difference in peak expiratory flow rates ^[4]	-0.59
95% Confidence Interval	( -2.55 to 1.36 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Tiotropium versus Salmeterol
[2]	Other relevant information, such as adjustments or degrees of freedom:
	MMRM (fixed terms: treatment, centre, week, treatmentweek; covariates: baseline PEFR, baseline PEFRweek)
[3]	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.
[4]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

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More Information

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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: Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.

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: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com

No publications provided by Boehringer Ingelheim Pharmaceuticals

Publications automatically indexed to this study:

Rabe KF, Fabbri LM, Vogelmeier C, Kögler H, Schmidt H, Beeh KM, Glaab T. Seasonal distribution of COPD exacerbations in the prevention of exacerbations with tiotropium in COPD trial. Chest. 2013 Mar;143(3):711-9.

Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011 Mar 24;364(12):1093-103.

Beeh KM, Hederer B, Glaab T, Müller A, Rutten-van Moelken M, Kesten S, Vogelmeier C. Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations. Int J Chron Obstruct Pulmon Dis. 2009;4:119-25. Epub 2009 Apr 15.

Responsible Party:	Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT00563381 History of Changes
Other Study ID Numbers:	205.389, EUDRACT2007-001840-33
Study First Received:	November 22, 2007
Results First Received:	March 29, 2011
Last Updated:	July 10, 2012
Health Authority:	Austria: AGES, Oesterreichische Agentur für Gesundheit und Ernaehrungssicherheit Belgium: AFMPS - Agence Fédérale des Médicaments et des Produits des Santé Bulgaria: Bulgarian Drug Agency Czech Republic: State Institute for Drug Control Denmark: The Danish Medicines Agency Finland: Finnish Medicines Agency France: AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) Germany: BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) Great Britain: Medicines and Heathcare Products Regulatory Agency Hungary: ORSZÁGOS GYÓGYSZERÉSZETI INTÉZET Israel: not applicable Italy: COMITATO ETICO DELLA PROVINCIA DI FERRARA Latvia: State Agency of Medicines Lithuania: Lithuanian Bioethics Committee Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Norway: Norwegian Medicines Agency Poland: Agency for Registration of Medicinal Products, Medical Devices & Biocides Portugal: INFARMED - Instituto Nacional da Farmácia e do Medicamento Romania: National Medicines Agency Russia: Federal Service On Surveillance In Healthcare And Social Development Of Russian Federation Slovakia: State Institute for Drug Control Slovenia: Agency for Medicinal Products and Medical Devices of the Republic of Slovenia Spain: Agencia Española de Medicamentos y Productos Sanitarios Turkey: Ministery Of Health / Central Ethics Committee Ukraine: The State Pharmacological Center of Ministry of Health of Ukraine United States: Food and Drug Administration

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