Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma I

This study has been completed.

Sponsor:

Collaborator:

Pfizer

Information provided by (Responsible Party):

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT01172808

First received: July 26, 2010

Last updated: June 3, 2014

Last verified: January 2014

History of Changes

Results First Received: October 25, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double-Blind; Primary Purpose: Treatment
Condition:	Asthma
Interventions:	Drug: Placebo Drug: tiotropium Respimat® low dose Drug: tiotropium Respimat® high dose Drug: 50 mcg salmeterol HFA MDI

Participant Flow

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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 was 1 patient in the TIO R5 group randomized but not treated.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Participant Flow: Overall Study

	Placebo	Tio R2.5	Tio R5	Salmeterol
STARTED	269 ^[1]	262 ^[1]	264 ^[1]	275 ^[1]
COMPLETED	248	249	241	260
NOT COMPLETED	21	13	23	15
Adverse Event	8	4	8	3
Lack of Efficacy	1	0	0	0
Protocol Violation	2	2	2	0
Lost to Follow-up	0	1	1	3
Withdrawal by Subject	4	1	3	2
Other	6	5	9	7

^[1]	Entered and Treated

Baseline Characteristics

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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.
Treated Set (TS) - all randomised patients who received at least 1 dose of randomised trial medication.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Total	Total of all reporting groups

Baseline Measures

	Placebo	Tio R2.5	Tio R5	Salmeterol	Total
Overall Participants Analyzed [Units: Participants]	269	262	264	275	1070

Age [Units: Years] Mean (Standard Deviation)	42.5 (13.1)	43.7 (13.1)	44.4 (12.6)	42.6 (12.6)	43.3 (12.9)

Gender [Units: Participants]
Female	166	156	154	159	635
Male	103	106	110	116	435

Outcome Measures

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1. Primary:

Peak FEV1 Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]

Measure Type	Primary
Measure Title	Peak FEV1 Within 3 Hours Post-dose Response
Measure Description	Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS) - all treated patients who had baseline data and at least 1 on-treatment efficacy measurement excluding patients from one centre due to non-compliance with good clinical practice.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
Peak FEV1 Within 3 Hours Post-dose Response [Units: Litre] Mean (Standard Error)	0.053 (0.021)	0.289 (0.021)	0.250 (0.021)	0.266 (0.020)

Statistical Analysis 1 for Peak FEV1 Within 3 Hours Post-dose Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.236
95% Confidence Interval	0.181 to 0.291
Standard Error of the mean	(0.028)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Peak FEV1 Within 3 Hours Post-dose Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.198
95% Confidence Interval	0.142 to 0.253
Standard Error of the mean	(0.028)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre , week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

2. Primary:

Trough FEV1 Response [ Time Frame: 24 weeks ]

Measure Type	Primary
Measure Title	Trough FEV1 Response
Measure Description	Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
Trough FEV1 Response [Units: Litre] Mean (Standard Error)	-0.036 (0.022)	0.148 (0.022)	0.115 (0.022)	0.086 (0.022)

Statistical Analysis 1 for Trough FEV1 Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.185
95% Confidence Interval	0.126 to 0.244
Standard Error of the mean	(0.030)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Trough FEV1 Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.152
95% Confidence Interval	0.092 to 0.211
Standard Error of the mean	(0.030)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

3. Primary:

The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

Measure Type	Primary
Measure Title	The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
Measure Description	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).
Time Frame	24 weeks

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 of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	518	515	513	535
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [Units: Percentage of participants]	57.7	64.5	64.3	66.5

Statistical Analysis 1 for The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Fisher Exact
P Value ^[4]	0.0308
Odds Ratio (OR) ^[5]	1.33
95% Confidence Interval	1.03 to 1.72

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method 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:
	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
[5]	Other relevant estimation information:
	Tio R2.5 / Placebo

Statistical Analysis 2 for The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Fisher Exact
P Value ^[4]	0.0348
Odds Ratio (OR) ^[5]	1.32
95% Confidence Interval	1.02 to 1.71

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method 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:
	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
[5]	Other relevant estimation information:
	Tio R5 / Placebo

4. Secondary:

Peak FVC Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Peak FVC Within 3 Hours Post-dose Response
Measure Description	Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
Peak FVC Within 3 Hours Post-dose Response [Units: Litre] Mean (Standard Error)	0.045 (0.022)	0.219 (0.022)	0.148 (0.023)	0.168 (0.022)

Statistical Analysis 1 for Peak FVC Within 3 Hours Post-dose Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.174
95% Confidence Interval	0.114 to 0.233
Standard Error of the mean	(0.030)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Peak FVC Within 3 Hours Post-dose Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0008
Mean Difference (Final Values) ^[5]	0.102
95% Confidence Interval	0.042 to 0.162
Standard Error of the mean	(0.031)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model. Spatial power used as covariance structure. The Kenward-Roger approximation was used to estimate denominator degrees of freedom.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

5. Secondary:

Trough FVC Response [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Trough FVC Response
Measure Description	Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
Trough FVC Response [Units: Litre] Mean (Standard Error)	-0.039 (0.025)	0.086 (0.026)	0.036 (0.026)	0.028 (0.025)

Statistical Analysis 1 for Trough FVC Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0001
Mean Difference (Final Values) ^[5]	0.125
95% Confidence Interval	0.062 to 0.189
Standard Error of the mean	(0.032)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Trough FVC Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0200
Mean Difference (Final Values) ^[5]	0.076
95% Confidence Interval	0.012 to 0.140
Standard Error of the mean	(0.033)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

6. Secondary:

FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response
Measure Description	Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response [Units: Litre] Mean (Standard Error)	-0.033 (0.020)	0.192 (0.020)	0.163 (0.020)	0.182 (0.020)

Statistical Analysis 1 for FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.224
95% Confidence Interval	0.171 to 0.278
Standard Error of the mean	(0.027)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.195
95% Confidence Interval	0.141 to 0.249
Standard Error of the mean	(0.027)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

7. Secondary:

FVC Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	FVC Area Under Curve 0-3 Hours (AUC0-3h) Response
Measure Description	Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
FVC Area Under Curve 0-3 Hours (AUC0-3h) Response [Units: Litre] Mean (Standard Error)	-0.066 (0.023)	0.092 (0.023)	0.041 (0.024)	0.062 (0.023)

Statistical Analysis 1 for FVC Area Under Curve 0-3 Hours (AUC0-3h) Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	0.158
95% Confidence Interval	0.100 to 0.215
Standard Error of the mean	(0.029)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for FVC Area Under Curve 0-3 Hours (AUC0-3h) Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0003
Mean Difference (Final Values) ^[5]	0.106
95% Confidence Interval	0.049 to 0.164
Standard Error of the mean	(0.029)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

8. Secondary:

Trough PEF Response [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Trough PEF Response
Measure Description	Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	250	247	241	259
Trough PEF Response [Units: Litre/min] Mean (Standard Error)	2.913 (3.641)	40.819 (3.664)	36.590 (3.712)	31.317 (3.596)

Statistical Analysis 1 for Trough PEF Response

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	37.907
95% Confidence Interval	28.113 to 47.700
Standard Error of the mean	(4.994)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Trough PEF Response

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	33.677
95% Confidence Interval	23.825 to 43.529
Standard Error of the mean	(5.023)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

9. Secondary:

Total Asthma Quality of Life Questionnaire (AQLQs)) Score [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Total Asthma Quality of Life Questionnaire (AQLQs)) Score
Measure Description	Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	247	246	242	260
Total Asthma Quality of Life Questionnaire (AQLQs)) Score [Units: Units on a scale] Mean (Standard Error)	5.449 (0.049)	5.522 (0.049)	5.519 (0.049)	5.654 (0.048)

Statistical Analysis 1 for Total Asthma Quality of Life Questionnaire (AQLQs)) Score

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.2717
Mean Difference (Final Values) ^[5]	0.073
95% Confidence Interval	-0.057 to 0.203
Standard Error of the mean	(0.066)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Total Asthma Quality of Life Questionnaire (AQLQs)) Score

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.2956
Mean Difference (Final Values) ^[5]	0.070
95% Confidence Interval	-0.061 to 0.201
Standard Error of the mean	(0.067)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

10. Secondary:

Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period
Measure Description	Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	247	247	242	259
Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period [Units: Units on a scale] Mean (Standard Error)	1.563 (0.043)	1.362 (0.043)	1.431 (0.044)	1.302 (0.043)

Statistical Analysis 1 for Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0007
Mean Difference (Final Values) ^[5]	-0.202
95% Confidence Interval	-0.318 to -0.085
Standard Error of the mean	(0.059)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0262
Mean Difference (Final Values) ^[5]	-0.133
95% Confidence Interval	-0.250 to -0.016
Standard Error of the mean	(0.060)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

11. Secondary:

The Responder Rate as Assessed by the ACQ [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	The Responder Rate as Assessed by the ACQ
Measure Description	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).
Time Frame	24 weeks

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	265	259	261	271
The Responder Rate as Assessed by the ACQ [Units: Percentage of Participants]	53.2	62.5	66.7	68.6

Statistical Analysis 1 for The Responder Rate as Assessed by the ACQ

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Fisher Exact
P Value ^[4]	0.0377
Odds Ratio (OR) ^[5]	1.47
95% Confidence Interval	1.02 to 2.11

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method 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:
	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
[5]	Other relevant estimation information:
	Tio R2.5 / Placebo

Statistical Analysis 2 for The Responder Rate as Assessed by the ACQ

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Fisher Exact
P Value ^[4]	0.0022
Odds Ratio (OR) ^[5]	1.76
95% Confidence Interval	1.22 to 2.54

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method 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:
	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
[5]	Other relevant estimation information:
	Tio R5 / Placebo

12. Secondary:

Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24
Measure Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	238	247	236	254
Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 [Units: Litre/min] Mean (Standard Error)	-10.159 (3.537)	20.432 (3.547)	13.501 (3.587)	22.467 (3.491)

Statistical Analysis 1 for Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	30.591
95% Confidence Interval	21.726 to 39.455
Standard Error of the mean	(4.520)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	23.660
95% Confidence Interval	14.772 to 32.549
Standard Error of the mean	(4.533)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

13. Secondary:

Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24
Measure Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	239	245	236	252
Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 [Units: Litre/min] Mean (Standard Error)	-9.181 (3.245)	18.978 (3.245)	15.188 (3.273)	19.727 (3.190)

Statistical Analysis 1 for Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	28.160
95% Confidence Interval	19.440 to 36.880
Standard Error of the mean	(4.447)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	24.370
95% Confidence Interval	15.619 to 33.120
Standard Error of the mean	(4.462)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

14. Secondary:

PEF Variability [ Time Frame: Last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	PEF Variability
Measure Description	PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	Last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	237	244	234	252
PEF Variability [Units: Percentage of mean PEF] Mean (Standard Error)	-1.400 (0.437)	-1.958 (0.434)	0.180 (0.441)	-2.300 (0.427)

Statistical Analysis 1 for PEF Variability

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.3550
Mean Difference (Final Values) ^[5]	-0.558
95% Confidence Interval	-1.740 to 0.624
Standard Error of the mean	(0.603)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for PEF Variability

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0094
Mean Difference (Final Values) ^[5]	1.580
95% Confidence Interval	0.388 to 2.771
Standard Error of the mean	(0.608)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

15. Secondary:

Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24
Measure Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	238	247	236	254
Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 [Units: Litre] Mean (Standard Error)	0.021 (0.022)	0.101 (0.022)	0.073 (0.022)	0.117 (0.021)

Statistical Analysis 1 for Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0069
Median Difference (Final Values) ^[5]	0.081
95% Confidence Interval	0.022 to 0.139
Standard Error of the mean	(0.030)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0810
Mean Difference (Final Values) ^[5]	0.052
95% Confidence Interval	-0.006 to 0.111
Standard Error of the mean	(0.030)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

16. Secondary:

Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24
Measure Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	239	245	236	252
Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 [Units: Litre] Mean (Standard Error)	-0.000 (0.022)	0.065 (0.022)	0.039 (0.022)	0.072 (0.022)

Statistical Analysis 1 for Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.0363
Mean Difference (Final Values) ^[5]	0.065
95% Confidence Interval	0.004 to 0.126
Standard Error of the mean	(0.031)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.2077
Mean Difference (Final Values) ^[5]	0.039
95% Confidence Interval	-0.022 to 0.100
Standard Error of the mean	(0.031)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

17. Secondary:

Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24
Measure Description	Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	239	247	236	254
Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 [Units: Number of Puffs] Mean (Standard Error)	-0.962 (0.102)	-1.124 (0.102)	-0.818 (0.103)	-1.416 (0.100)

Statistical Analysis 1 for Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.2447
Mean Difference (Final Values) ^[5]	-0.162
95% Confidence Interval	-0.436 to 0.111
Standard Error of the mean	(0.140)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.3046
Mean Difference (Final Values) ^[5]	0.144
95% Confidence Interval	-0.131 to 0.419
Standard Error of the mean	(0.140)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

18. Secondary:

Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

Measure Type	Secondary
Measure Title	Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24
Measure Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.
Time Frame	Baseline and last 7 days before week 24 visit

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

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	239	247	236	254
Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 [Units: Days] Mean (Standard Error)	0.162 (0.021)	0.207 (0.021)	0.157 (0.021)	0.266 (0.021)

Statistical Analysis 1 for Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R2.5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.1178
Mean Difference (Final Values) ^[5]	0.045
95% Confidence Interval	-0.011 to 0.102
Standard Error of the mean	(0.029)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R2.5 - Placebo

Statistical Analysis 2 for Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24

Groups ^[1]	Placebo vs. Tio R5
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.8880
Mean Difference (Final Values) ^[5]	-0.004
95% Confidence Interval	-0.061 to 0.053
Standard Error of the mean	(0.029)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
[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:
	Tio R5 - Placebo

19. Secondary:

Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
Measure Description	Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).
Time Frame	24 weeks

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 of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	518	515	513	535
Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [Units: Weeks] Median (95% Confidence Interval)	NA ^[1]	NA ^[1]	NA ^[1]	NA ^[1]

[1]	The median time to first severe asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.

No statistical analysis provided for Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

20. Secondary:

Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Title	Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
Measure Description	Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
Time Frame	24 weeks

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 of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Measured Values

	Placebo	Tio R2.5	Tio R5	Salmeterol
Participants Analyzed [Units: Participants]	518	515	513	535
Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [Units: Weeks] Median (95% Confidence Interval)	NA ^[1]	NA ^[1]	NA ^[1]	NA ^[1]

[1]	The median time to first asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.

No statistical analysis provided for Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

Hide Limitations and Caveats

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

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, Engel M, Bour L, Verkleij CB, Moroni-Zentgraf P, Bateman ED. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015 May;3(5):367-76. doi: 10.1016/S2213-2600(15)00031-4. Epub 2015 Feb 12.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01172808 History of Changes
Other Study ID Numbers:	205.418 2009-018004-18 ( EudraCT Number: EudraCT )
Study First Received:	July 26, 2010
Results First Received:	October 25, 2013
Last Updated:	June 3, 2014

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