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Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Moderate Persistent Asthma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Asthma
Interventions Drug: Tiotropium low dose QD
Drug: Tiotropium high dose QD
Drug: Placebo
Enrollment 403
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide 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.
Period Title: Overall Study
Started 132 136 135
Completed 122 130 130
Not Completed 10 6 5
Reason Not Completed
Non compliant with protocol             1             0             0
Consent withdrawn not due to AE             4             3             2
Other             4             0             3
Lost to Follow-up             0             2             0
Not treated             1             1             0
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5 Total
Hide 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
Hide 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%
1.Primary Outcome
Title FEV1 Peak (0-3h) Change From Baseline
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Show Statistical Analysis 5 Hide 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
Show Statistical Analysis 6 Hide 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
Show Statistical Analysis 7 Hide 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
Show Statistical Analysis 8 Hide 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
Show Statistical Analysis 9 Hide 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
Show Statistical Analysis 10 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Show Statistical Analysis 5 Hide 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
Show Statistical Analysis 6 Hide 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
Show Statistical Analysis 7 Hide 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
Show Statistical Analysis 8 Hide 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
Show Statistical Analysis 9 Hide 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
Show Statistical Analysis 10 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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: Number
Unit 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Show Statistical Analysis 2 Hide 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
Show Statistical Analysis 3 Hide 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
Show Statistical Analysis 4 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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: Number
Unit 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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=122, 130, 130) -0.070  (0.030) -0.079  (0.029) -0.144  (0.029)
Week 48 (N=119, 122, 125) -0.101  (0.030) -0.131  (0.029) -0.127  (0.029)
Show Statistical Analysis 1 Hide 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