Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Moderate Persistent Asthma
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ClinicalTrials.gov Identifier: NCT01634139
Recruitment Status :
Completed

First Posted : July 6, 2012

Results First Posted : July 12, 2016

Last Update Posted : July 12, 2016

Sponsor:

Collaborator:

Information provided by (Responsible Party):

Boehringer Ingelheim

Interventional
Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
Asthma
Drug: Tiotropium low dose QD
Drug: Tiotropium high dose QD
Drug: Placebo
403

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Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Total
Arm/Group Description
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Total of all reporting groups
Arm/Group Description
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Total of all reporting groups
Overall Number of Baseline Participants
131
135
135
401
Baseline Analysis Population Description
...
Baseline Analysis Population Description
Treated Set (TS): This patient set included all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of investigational treatment.

Age, Continuous
Mean (Standard Deviation)

Unit of measure: Years

Number Analyzed
131 participants
135 participants
135 participants
401 participants
9.0
(1.6)
9.0
(1.6)
8.9
(1.7)
8.9
(1.6)
Sex: Female, Male
Measure Type: Count of Participants

Unit of measure: Participants

Number Analyzed
131 participants
135 participants
135 participants
401 participants
Female
46

35.1%

38

28.1%

53

39.3%

137

34.2%

Male
85

64.9%

97

71.9%

82

60.7%

264

65.8%

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1.Primary Outcome
Title
FEV1 Peak (0-3h) Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 24.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

Time Frame
Baseline and 24 Weeks.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
Full Analysis Set (FAS) was equal to treated set which included all randomised patients who received at least 1 documented dose of study medication. Missing data at a visit was imputed by available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
126
131
134
Mean (Standard Error)Unit of Measure: Litres (L)

0.225
(0.027)
0.395
(0.026)
0.389
(0.026)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.170
Confidence Interval
(2-Sided) 95%
0.108
to 0.231

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.031

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.164
Confidence Interval
(2-Sided) 95%
0.103
to 0.255

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.031

Estimation Comments
Difference calculated as Tio R5 minus placebo

2.Secondary Outcome
Title
Trough FEV1 Change From Baseline
Description
Change from Baseline in ...

Description
Change from Baseline in Trough (pre-dose) Forced Expiratory Volume (FEV) in 1 second (FEV1) measured at week 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
Full Analysis Set (FAS) was equal to treated set which included all randomised patients who received at least 1 documented dose of study medication. Missing data at a visit was imputed by available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

Week 24 (N=126, 131, 134)
0.156
(0.031)
0.272
(0.030)
0.274
(0.030)
Week 48 (N=124, 130, 130)
0.266
(0.032)
0.337
(0.030)
0.365
(0.031)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0012
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.116
Confidence Interval
(2-Sided) 95%
0.046
to 0.186

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0010
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.118
Confidence Interval
(2-Sided) 95%
0.048
to 0.188

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0477
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.071
Confidence Interval
(2-Sided) 95%
0.001
to 0.142

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0059
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.099
Confidence Interval
(2-Sided) 95%
0.029
to 0.170

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R5 minus placebo

3.Secondary Outcome
Title
FEV1 Peak (0-3h) at Week 48 Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

Time Frame
Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS. Missing data at a visit was imputed by available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
124
130
130
Mean (Standard Error)Unit of Measure: Litres (L)

0.351
(0.027)
0.474
(0.026)
0.477
(0.026)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
[Not Specified]
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.124
Confidence Interval
(2-Sided) 95%
0.062
to 0.185

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.031

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
[Not Specified]
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.127
Confidence Interval
(2-Sided) 95%
0.065
to 0.188

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.031

Estimation Comments
Difference calculated as Tio R5 minus placebo

4.Secondary Outcome
Title
FEV1 AUC (0-3h) Change From Baseline
Description
Change from baseline of ...

Description
Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

Time Frame
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at week 24

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
126
131
134
Mean (Standard Error)Unit of Measure: Litres (L)

0.152
(0.026)
0.306
(0.025)
0.309
(0.025)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.154
Confidence Interval
(2-Sided) 95%
0.095
to 0.212

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.030

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.157
Confidence Interval
(2-Sided) 95%
0.098
to 0.215

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.030

Estimation Comments
Difference calculated as Tio R5 minus placebo

5.Secondary Outcome
Title
FEV1 Change From Baseline at Each Individual Timepoint
Description
FEV1 change from baselin...

Description
FEV1 change from baseline to week 24 at each individual timepoint.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

10 minutes pre-dose (Week 24) (N=126, 131, 134)
0.156
(0.031)
0.272
(0.030)
0.274
(0.030)
30 minutes post-dose (Week 24) (N=126, 131, 134)
0.156
(0.027)
0.295
(0.026)
0.307
(0.027)
1 hour post-dose (Week 24) (N=126, 131, 134)
0.165
(0.028)
0.313
(0.027)
0.312
(0.027)
2 hours post-dose (Week 24) (N=126, 131, 134)
0.144
(0.028)
0.307
(0.027)
0.312
(0.027)
3 hours post-dose (Week 24) (N=126, 131, 134)
0.147
(0.027)
0.325
(0.026)
0.322
(0.026)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
10 minutes pre-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0012
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.116
Confidence Interval
(2-Sided) 95%
0.046
to 0.186

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
10 minutes pre-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0010
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.118
Confidence Interval
(2-Sided) 95%
0.048
to 0.188

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.036

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
30 minutes post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.139
Confidence Interval
(2-Sided) 95%
0.076
to 0.201

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
30 minutes post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.151
Confidence Interval
(2-Sided) 95%
0.088
to 0.213

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 5
Statistical Analysis 5
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
1 hour post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.148
Confidence Interval
(2-Sided) 95%
0.084
to 0.211

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 6
Statistical Analysis 6
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
1 hour post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.147
Confidence Interval
(2-Sided) 95%
0.084
to 0.210

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 7
Statistical Analysis 7
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
2 hours post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.163
Confidence Interval
(2-Sided) 95%
0.101
to 0.226

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 8
Statistical Analysis 8
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
2 hours post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.168
Confidence Interval
95%
0.106
to 0.231

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 9
Statistical Analysis 9
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
3 hours post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.178
Confidence Interval
(2-Sided) 95%
0.116
to 0.240

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 10
Statistical Analysis 10
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
3 hours post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
<0.0001
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.176
Confidence Interval
(2-Sided) 95%
0.114
to 0.238

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.032

Estimation Comments
Difference calculated as Tio R5 minus placebo

6.Secondary Outcome
Title
FVC Peak(0-3h) Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 24 and 48 Weeks of treatment.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

Week 24 (N=124, 130, 134)
0.215
(0.033)
0.325
(0.032)
0.307
(0.032)
Week 48 (N=124, 130, 130)
0.361
(0.033)
0.430
(0.032)
0.413
(0.032)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0036
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.110
Confidence Interval
(2-Sided) 95%
0.036
to 0.184

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.038

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0152
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.091
Confidence Interval
(2-Sided) 95%
0.018
to 0.165

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0687
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.069
Confidence Interval
(2-Sided) 95%
-0.005
to 0.143

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.038

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1666
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.052
Confidence Interval
(2-Sided) 95%
-0.022
to 0.126

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.038

Estimation Comments
Difference calculated as Tio R5 minus placebo

7.Secondary Outcome
Title
Trough FVC Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in Trough (pre-dose) FVC measured at week 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

Week 24 (N=126, 131, 134)
0.154
(0.035)
0.246
(0.034)
0.206
(0.034)
Week 48 (N=124, 130, 130)
0.280
(0.035)
0.341
(0.034)
0.333
(0.034)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0228
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.092
Confidence Interval
(2-Sided) 95%
0.013
to 0.171

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1980
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.052
Confidence Interval
(2-Sided) 95%
-0.027
to 0.131

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1256
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.062
Confidence Interval
(2-Sided) 95%
-0.017
to 0.141

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1880
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.053
Confidence Interval
(2-Sided) 95%
-0.026
to 0.133

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R5 minus placebo

8.Secondary Outcome
Title
FVC AUC (0-3h) Change From Baseline
Description
Change from baseline of ...

Description
Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

Time Frame
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
126
131
134
Mean (Standard Error)Unit of Measure: Litres (L)

0.130
(0.030)
0.235
(0.029)
0.207
(0.029)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0023
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.105
Confidence Interval
(2-Sided) 95%
0.037
to 0.172

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.034

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0255
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.076
Confidence Interval
(2-Sided) 95%
0.009
to 0.143

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.034

Estimation Comments
Difference calculated as Tio R5 minus placebo

9.Secondary Outcome
Title
FVC Change From Baseline at Each Individual Timepoint
Description
FVC change from baseline...

Description
FVC change from baseline to week 24 at each individual timepoint.

The measured values presented are actually adjusted means

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at Week 24

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

10 minutes pre-dose (Week 24) (N=124, 131, 134)
0.154
(0.035)
0.246
(0.034)
0.206
(0.034)
30 minutes post-dose (Week 24) (N=124, 131, 134)
0.144
(0.032)
0.222
(0.031)
0.211
(0.031)
1 hour post-dose (Week 24) (N=124, 131, 134)
0.142
(0.032)
0.252
(0.031)
0.202
(0.031)
2 hours post-dose (Week 24) (N=124, 131, 134)
0.117
(0.033)
0.230
(0.031)
0.210
(0.032)
3 hours post-dose (Week 24) (N=124, 131, 134)
0.118
(0.033)
0.233
(0.032)
0.210
(0.032)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
10 minutes pre-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0228
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.092
Confidence Interval
(2-Sided) 95%
0.013
to 0.171

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
10 minutes pre-dose.(Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1980
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.052
Confidence Interval
(2-Sided) 95%
-0.027
to 0.131

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.040

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
30 minutes post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0344
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.078
Confidence Interval
(2-Sided) 95%
0.006
to 0.150

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
30 minutes post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0696
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.067
Confidence Interval
(2-Sided) 95%
-0.005
to 0.139

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 5
Statistical Analysis 5
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
1 hour post-dose (week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0032
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.109
Confidence Interval
(2-Sided) 95%
0.037
to 0.182

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 6
Statistical Analysis 6
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
1 hour post-dose (week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1044
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.060
Confidence Interval
(2-Sided) 95%
-0.012
to 0.132

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 7
Statistical Analysis 7
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
2 hours post-dose (week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0027
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.113
Confidence Interval
(2-Sided) 95%
0.039
to 0.186

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 8
Statistical Analysis 8
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
2 hours post-dose (week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0130
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.093
Confidence Interval
(2-Sided) 95%
0.020
to 0.166

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.037

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 9
Statistical Analysis 9
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
3 hours post-dose (week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0025
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Median Difference (Net)
Estimated Value
0.115
Confidence Interval
(2-Sided) 95%
0.041
to 0.190

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.038

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 10
Statistical Analysis 10
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
3 hours post-dose (Week 24)
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0156
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.092
Confidence Interval
(2-Sided) 95%
0.017
to 0.166

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.038

Estimation Comments
Difference calculated as Tio R5 minus placebo

10.Secondary Outcome
Title
Use of PRN (Pro re Nata) Rescue Medication Per Day
Description
Change from baseline in ...

Description
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at weeks 24 and 48.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Number of puffs of rescue medication

Week 24 (N=122, 130, 133)
-0.437
(0.079)
-0.603
(0.077)
0.646
(0.077)
Week 48 (N=120, 123, 127)
-0.484
(0.079)
0.638
(0.078)
0.685
(0.078)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1349
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.165
Confidence Interval
(2-Sided) 95%
-0.382
to 0.051

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.110

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0588
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.209
Confidence Interval
(2-Sided) 95%
-0.425
to 0.008

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.110

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1675
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.154
Confidence Interval
(2-Sided) 95%
-0.372
to 0.065

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.111

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0709
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.201
Confidence Interval
(2-Sided) 95%
-0.419
to 0.017

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.111

Estimation Comments
Difference calculated as Tio R5 minus placebo

11.Secondary Outcome
Title
Use of PRN Rescue Medication During Daytime
Description
Change from baseline in ...

Description
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during daytime based on the weekly mean at weeks 24 and 48.

Measured values presented are actually adjusted means

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Number of puffs of rescue medication

Week 24 (N=121, 130, 133)
-0.234
(0.055)
-0.350
(0.053)
-0.375
(0.053)
Week 48 (N=119, 123, 125)
-0.247
(0.055)
-0.372
(0.053)
-0.378
(0.053)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0749
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.116
Confidence Interval
(2-Sided) 95%
-0.245
to 0.012

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.065

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0305
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.141
Confidence Interval
(2-Sided) 95%
-0.269
to -0.013

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.065

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0581
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.125
Confidence Interval
(2-Sided) 95%
-0.255
to 0.004

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.066

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0464
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.131
Confidence Interval
(2-Sided) 95%
-0.260
to -0.002

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.066

Estimation Comments
Difference calculated as Tio R5 minus placebo

12.Secondary Outcome
Title
Use of PRN Rescue Medication During Nighttime
Description
Change from baseline in ...

Description
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during nighttime based on the weekly mean at weeks 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Number of puffs of rescue medication

Week 24 (N=122, 130, 130)
-0.178
(0.051)
-0.274
(0.050)
-0.304
(0.050)
Week 48 (N=119, 122, 125)
-0.198
(0.052)
-0.298
(0.050)
-0.301
(0.050)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1182
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.096
Confidence Interval
(2-Sided) 95%
-0.217
to 0.025

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.062

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0404
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.126
Confidence Interval
(2-Sided) 95%
-0.246
to -0.006

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.061

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1105
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.099
Confidence Interval
(2-Sided) 95%
-0.221
to 0.023

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.062

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0983
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.103
Confidence Interval
(2-Sided) 95%
-0.224
to 0.019

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.062

Estimation Comments
Difference calculated as Tio R5 minus placebo

13.Secondary Outcome
Title
Peak Expiratory Flow (PEF) a.m. Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres per min (L/min)

Week 24 (N=122, 130, 130)
14.153
(4.556)
22.660
(4.406)
21.646
(4.434)
Week 48 (N=119, 122, 125)
20.824
(4.581)
26.362
(4.440)
29.598
(4.466)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1146
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
8.507
Confidence Interval
(2-Sided) 95%
-2.063
to 19.077

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.387

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1628
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
7.493
Confidence Interval
(2-Sided) 95%
-3.034
to 18.020

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.365

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.3085
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
5.538
Confidence Interval
(2-Sided) 95%
-5.127
to 16.203

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.435

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1053
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
8.774
Confidence Interval
(2-Sided) 95%
-1.847
to 19.394

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.413

Estimation Comments
Difference calculated as Tio R5 minus placebo

14.Secondary Outcome
Title
PEF p.m. Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres per min (L/min)

Week 24 (N= 121, 130, 133)
3.179
(4.597)
15.539
(4.444)
17.325
(4.464)
Week 48 (N=119, 123, 125)
17.100
(4.622)
15.219
(4.475)
21.276
(4.504)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0236
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
12.360
Confidence Interval
(2-Sided) 95%
1.663
to 23.056

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.451

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0093
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
14.146
Confidence Interval
(2-Sided) 95%
3.497
to 24.794

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.427

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.7322
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-1.882
Confidence Interval
(2-Sided) 95%
-12.667
to 8.904

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.497

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.4463
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
4.176
Confidence Interval
(2-Sided) 95%
-6.578
to 14.929

Parameter Dispersion
Type: Standard Error of the mean

Value: 5.481

Estimation Comments
Difference calculated as Tio R5 minus placebo

15.Secondary Outcome
Title
PEF Variability Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in the peak expiratory flow variability based on the weekly mean at week 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Percentage of PEF

Week 24 (N=121, 129, 128)
-1.204
(0.826)
-0.942
(0.798)
-1.038
(0.803)
Week 48 (N=117, 120, 121)
-0.320
(0.835)
-0.048
(0.814)
-0.899
(0.818)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.8008
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.262
Confidence Interval
(2-Sided) 95%
-1.775
to 2.299

Parameter Dispersion
Type: Standard Error of the mean

Value: 1.039

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.8731
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.166
Confidence Interval
(2-Sided) 95%
-1.875
to 2.208

Parameter Dispersion
Type: Standard Error of the mean

Value: 1.041

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.7975
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.272
Confidence Interval
(2-Sided) 95%
-1.803
to 2.346

Parameter Dispersion
Type: Standard Error of the mean

Value: 1.058

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.5845
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.579
Confidence Interval
(2-Sided) 95%
-2.656
to 1.498

Parameter Dispersion
Type: Standard Error of the mean

Value: 1.059

Estimation Comments
Difference calculated as Tio R5 minus placebo

16.Secondary Outcome
Title
FEV1 a.m Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 24 and 48.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres

Week 24 (N=122, 130, 130)
0.191
(0.041)
0.209
(0.039)
0.126
(0.039)
Week 48 (N=119, 122, 125)
0.236
(0.041)
0.259
(0.040)
0.221
(0.040)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.6932
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.019
Confidence Interval
(2-Sided) 95%
-0.075
to 0.113

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.048

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1741
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.065
Confidence Interval
(2-Sided) 95%
-0.158
to 0.029

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.048

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.6250
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.024
Confidence Interval
(2-Sided) 95%
-0.071
to 0.118

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.048

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.7597
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.015
Confidence Interval
(2-Sided) 95%
-0.109
to 0.080

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.048

Estimation Comments
Difference calculated as Tio R5 minus placebo

17.Secondary Outcome
Title
FEV1 p.m. Change From Baseline
Description
Change from baseline in ...

Description
Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 24 and 48.

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Litres (L)

Week 24 (N=121, 129, 128)
0.167
(0.042)
0.142
(0.041)
0.092
(0.041)
Week 48 (N=119, 123, 125)
0.202
(0.042)
0.208
(0.041)
0.159
(0.041)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.6166
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.025
Confidence Interval
(2-Sided) 95%
-0.122
to 0.073

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.050

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1267
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.076
Confidence Interval
(2-Sided) 95%
-0.173
to 0.021

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.049

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.9000
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.006
Confidence Interval
(2-Sided) 95%
-0.092
to 0.105

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.050

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.3897
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.043
Confidence Interval
(2-Sided) 95%
-0.141
to 0.055

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.050

Estimation Comments
Difference calculated as Tio R5 minus placebo

18.Secondary Outcome
Title
ACQ−IA Total Score
Description
Interviewer Administered...

Description
Interviewer Administered Asthma Control Questionnaire (ACQ-IA) total score after 24 and 48 weeks of treatment.

The ACQ-IA is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ-IA total score is calculated as the mean of the responses to all 7 questions.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Units on a Scale

Week 24 (N=126, 131, 134)
1.017
(0.062)
0.897
(0.060)
0.835
(0.060)
Week 48 (N=124, 130, 130)
0.817
(0.062)
0.752
(0.060)
0.723
(0.061)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0975
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.120
Confidence Interval
(2-Sided) 95%
-0.262
to 0.022

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.072

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0116
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.182
Confidence Interval
(2-Sided) 95%
-0.323
to -0.041

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.072

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.3732
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.065
Confidence Interval
(2-Sided) 95%
-0.208
to 0.078

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.073

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1985
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.093
Confidence Interval
(2-Sided) 95%
-0.236
to 0.049

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.073

Estimation Comments
Difference calculated as Tio R5 minus placebo

19.Secondary Outcome
Title
ACQ−IA Responder Analysis
Description
Responder categories bas...

Description
Responder categories based on the ACQ-IA total score after 24 and 48 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5). No statistical testing was performed for ACQ-IA total score responders.

The ACQ-IA is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.

Time Frame
Weeks 24 and 48

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Measure Type: NumberUnit of Measure: Patients

Responders at Week 24
97
108
118
No Change at Week 24
34
27
16
Worsening at Week 24
0
0
1
Responder at Week 48
114
118
117
No Change at Week 48
16
14
17
Worsening at Week 48
1
3
1

20.Secondary Outcome
Title
PAQLQ(S) Total Score
Description
Standardised Paediatric ...

Description
Standardised Paediatric Asthma Quality of Life Questionnaire (PAQLQ(S)) total score at weeks 24 and 48.

The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). Total Score is calculated as mean of all 23 questions.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Units on a Scale

Week 24 (N= 126, 131, 134)
5.966
(0.065)
6.142
(0.063)
6.093
(0.062)
Week 48 (N=124, 130, 130)
6.309
(0.065)
6.288
(0.063)
6.327
(0.063)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0144
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.176
Confidence Interval
(2-Sided) 95%
0.035
to 0.316

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.072

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0747
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.127
Confidence Interval
(2-Sided) 95%
-0.013
to 0.267

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.071

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.7654
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.021
Confidence Interval
(2-Sided) 95%
-0.163
to 0.120

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.072

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.8082
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.017
Confidence Interval
(2-Sided) 95%
-0.124
to 0.158

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.072

Estimation Comments
Difference calculated as Tio R5 minus placebo

21.Secondary Outcome
Title
PAQLQ(S) Symptom Domain Score
Description
PAQLQ(S) symptom domain ...

Description
PAQLQ(S) symptom domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score was calculated as the mean of the items in the domain.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Units on a Scale

Week 24 (N=126, 131, 134)
5.840
(0.076)
6.015
(0.074)
5.967
(0.073)
Week 48 (N=124, 130, 130)
6.195
(0.076)
6.177
(0.074)
6.199
(0.074)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0392
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.175
Confidence Interval
(2-Sided) 95%
0.009
to 0.341

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.085

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1351
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.126
Confidence Interval
(2-Sided) 95%
-0.039
to 0.292

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.084

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.8291
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.018
Confidence Interval
(2-Sided) 95%
-0.185
to 0.149

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.085

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.9655
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.004
Confidence Interval
(2-Sided) 95%
-0.163
to 0.171

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.085

Estimation Comments
Difference calculated as Tio R5 minus placebo

22.Secondary Outcome
Title
PAQLQ(S) Activity Limitation Domain Score
Description
PAQLQ(S) activity limita...

Description
PAQLQ(S) activity limitation domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Units on a Scale

Week 24 (N= 126, 131, 134)
5.898
(0.069)
6.089
(0.067)
6.023
(0.067)
Week 48 (N=124, 130, 130)
6.249
(0.070)
6.284
(0.068)
6.319
(0.067)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0139
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.191
Confidence Interval
(2-Sided) 95%
0.039
to 0.343

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.077

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.1043
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.125
Confidence Interval
(2-Sided) 95%
-0.026
to 0.276

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.077

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.6547
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.035
Confidence Interval
(2-Sided) 95%
-0.118
to 0.187

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.078

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.3648
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.070
Confidence Interval
(2-Sided) 95%
-0.082
to 0.222

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.077

Estimation Comments
Difference calculated as Tio R5 minus placebo

23.Secondary Outcome
Title
PAQLQ(S) Emotional Function Domain Score
Description
PAQLQ(S) emotional funct...

Description
PAQLQ(S) emotional function domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain.

The measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Mean (Standard Error)Unit of Measure: Units on a Scale

Week 24 (N=126, 131, 134)
6.157
(0.067)
6.323
(0.065)
6.298
(0.064)
Week 48 (N=124, 130, 130)
6.481
(0.067)
6.420
(0.065)
6.491
(0.065)

Statistical Analysis 1
Statistical Analysis 1
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0256
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.166
Confidence Interval
(2-Sided) 95%
0.020
to 0.312

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.074

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 2
Statistical Analysis 2
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 24
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.0561
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.141
Confidence Interval
(2-Sided) 95%
-0.004
to 0.286

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.074

Estimation Comments
Difference calculated as Tio R5 minus placebo

Statistical Analysis 3
Statistical Analysis 3
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R2.5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.4127
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
-0.061
Confidence Interval
(2-Sided) 95%
-0.208
to 0.085

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.075

Estimation Comments
Difference calculated as Tio R2.5 minus placebo

Statistical Analysis 4
Statistical Analysis 4
Statistical Analysis Overview
Comparison Group Selection
Placebo Respimat, Tio R5
Comments
Week 48
Type of
Statistical Test
Superiority or Other
Comments
[Not Specified]
Statistical Test of Hypothesis
P-Value
0.8922
Comments
[Not Specified]
Method
Mixed Models Analysis
Comments
Repeated measures restricted maximum likelihood model
Method of Estimation
Estimation Parameter
Mean Difference (Net)
Estimated Value
0.010
Confidence Interval
(2-Sided) 95%
-0.136
to 0.156

Parameter Dispersion
Type: Standard Error of the mean

Value: 0.074

Estimation Comments
Difference calculated as Tio R5 minus placebo

24.Secondary Outcome
Title
Responders in PAQLQ(S) at Weeks 24 and 48
Description
Responders in PAQLQ(S) a...

Description
Responders in PAQLQ(S) at weeks 24 and 48. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≥0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≤-0.5). No statistical testing was performed for PAQLQ(S) total score responders.

The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control).

Time Frame
Weeks 24 and 48.

Outcome Measure Data Outcome Measure Data
Analysis Population Description
Analysis Population Description
FAS, missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason.

Arm/Group Title
Placebo Respimat
Tio R2.5
Tio R5
Arm/Group Description :
Inhalation of placebo solution (2 p...
Inhalation of 2.5mcg tiotropium (Ti...
Inhalation of 5mcg tiotropium (Tio ...
Arm/Group Description :
Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Overall Number of Participants Analyzed
131
135
135
Measure Type: NumberUnit of Measure: Patients

Responders at Week 24
67
82
73
No Change at Week 24
58
47
56
Worsening at Week 24
6
6
6
Responders at Week 48
89
96
92
No Change at Week 48
39
33
42
Worsening at Week 48
3
6
1

25.Secondary Outcome
Title
Change From Baseline in Nighttime Awakenings
Description
Change from baseline in ...

Description
Change from baseline in nighttime awakenings based on the weekly mean at weeks 24 and 48.

Nighttime awakenings was assessed by the question "Did you wake up during the night due to your asthma?" from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).

Measured values presented are actually adjusted means.

The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

Time Frame
Baseline and Week 24, Baseline and Week 48.