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Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Severe 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: NCT01634152
Recruitment Status : Completed
First Posted : July 6, 2012
Results First Posted : December 21, 2015
Last Update Posted : January 29, 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: Placebo
Drug: Tiotropium low dose mcg
Drug: Tiotropium high dose
Enrollment 401
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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Period Title: Overall Study
Started 134 137 130
Completed 130 136 126
Not Completed 4 1 4
Reason Not Completed
Adverse Event             2             0             2
Consent withdrawn not due to AE             1             0             1
Not treated             0             1             0
Other reason not defined above             1             0             1
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5 Total
Hide Arm/Group Description Inhalation of placebo solution (2 puffs) once daily for 12 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 12 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 12 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 134 136 130 400
Hide Baseline Analysis Population Description
Treated set which 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 134 participants 136 participants 130 participants 400 participants
9.1  (1.6) 8.8  (1.7) 9.2  (1.6) 9.0  (1.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 134 participants 136 participants 130 participants 400 participants
Female
41
  30.6%
40
  29.4%
40
  30.8%
121
  30.3%
Male
93
  69.4%
96
  70.6%
90
  69.2%
279
  69.8%
1.Primary Outcome
Title FEV1 Peak(0-3h) Change From Baseline
Hide Description

Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.252  (0.025) 0.287  (0.025) 0.391  (0.026)
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 0.2724
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%
-0.028 to 0.099
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.139
Confidence Interval (2-Sided) 95%
0.075 to 0.203
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
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 in 1 second (FEV1) measured at week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.136  (0.027) 0.154  (0.026) 0.223  (0.027)
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 for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. 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 0.5898
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.018
Confidence Interval (2-Sided) 95%
-0.048 to 0.085
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. 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 0.0117
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.087
Confidence Interval (2-Sided) 95%
0.019 to 0.154
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Difference calculated as Tio R5 minus placebo
3.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 12 weeks of treatment.

The measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.244  (0.028) 0.201  (0.027) 0.275  (0.028)
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 0.2277
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%
-0.113 to 0.027
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.3998
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.030
Confidence Interval (2-Sided) 95%
-0.040 to 0.101
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Difference calculated as Tio R5 minus placebo
4.Secondary Outcome
Title Trough FVC Change From Baseline
Hide Description

Change from baseline in Trough (pre-dose) FVC measured at week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.141  (0.029) 0.094  (0.029) 0.150  (0.030)
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 0.2030
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.048
Confidence Interval (2-Sided) 95%
-0.121 to 0.026
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.8194
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.009
Confidence Interval (2-Sided) 95%
-0.066 to 0.083
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.038
Estimation Comments Difference calculated as Tio R5 minus placebo
5.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 12 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.

Time Frame Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.175  (0.023) 0.206  (0.022) 0.301  (0.023)
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 0.2907
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.031
Confidence Interval (2-Sided) 95%
-0.026 to 0.088
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.126
Confidence Interval (2-Sided) 95%
0.068 to 0.184
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Difference calculated as Tio R5 minus placebo
6.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 12 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.

Time Frame Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
0.145  (0.025) 0.105  (0.024) 0.182  (0.025)
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 0.2008
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.041
Confidence Interval (2-Sided) 95%
-0.103 to 0.022
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.2545
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.037
Confidence Interval (2-Sided) 95%
-0.026 to 0.100
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Difference calculated as Tio R5 minus placebo
7.Secondary Outcome
Title FEV1 Change From Baseline at Each Individual Timepoint
Hide Description

Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint.

The measured values presented are actually adjusted means.

Time Frame Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
10 minutes pre-dose 0.136  (0.027) 0.154  (0.026) 0.223  (0.027)
30 minutes post-dose 0.166  (0.024) 0.202  (0.023) 0.285  (0.024)
1 hour post-dose 0.177  (0.025) 0.203  (0.024) 0.300  (0.025)
2 hours post-dose 0.191  (0.025) 0.216  (0.025) 0.324  (0.026)
3 hours post-dose 0.168  (0.026) 0.215  (0.026) 0.308  (0.026)
8.Secondary Outcome
Title FVC Change From Baseline at Each Individual Timepoint
Hide Description

FVC change from baseline at each individual timepoint.

The measured values presented are actually adjusted means.

Time Frame Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 135 128
Mean (Standard Error)
Unit of Measure: Litres
10 minutes pre-dose 0.141  (0.029) 0.094  (0.029) 0.150  (0.030)
30 minutes post-dose 0.130  (0.026) 0.096  (0.026) 0.164  (0.027)
1 hour post-dose 0.146  (0.027) 0.097  (0.026) 0.181  (0.027)
2 hours post-dose 0.159  (0.028) 0.113  (0.027) 0.199  (0.028)
3 hours post-dose 0.132  (0.028) 0.110  (0.028) 0.176  (0.029)
9.Secondary Outcome
Title Control of Asthma as Assessed by ACQ-IA Total Score
Hide Description

Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12.

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.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 130 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
1.026  (0.060) 1.046  (0.059) 0.948  (0.061)
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 0.7980
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.020
Confidence Interval (2-Sided) 95%
-0.133 to 0.173
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.078
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.3166
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.079
Confidence Interval (2-Sided) 95%
-0.233 to 0.076
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.079
Estimation Comments Difference calculated as Tio R5 minus placebo
10.Secondary Outcome
Title ACQ-IA Total Score Responders
Hide Description

Responder categories based on the ACQ-IA total score after 12 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 12 weeks
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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 134 136 130
Measure Type: Number
Unit of Measure: Percentage of participants
Responder 76.9 79.4 80.8
No change 20.9 18.4 16.2
Worsening 2.2 2.2 3.1
11.Secondary Outcome
Title Use of PRN 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 week 12.

The measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 127
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.570  (0.096) -0.553  (0.094) -0.660  (0.097)
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 0.8916
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%
-0.227 to 0.261
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.124
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.4789
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.089
Confidence Interval (2-Sided) 95%
-0.336 to 0.158
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.126
Estimation Comments Difference calculated as Tio R5 minus placebo
12.Secondary Outcome
Title Use of PRN Rescue Medication During the Daytime
Hide Description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.279  (0.057) -0.294  (0.055) -0.365  (0.057)
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 0.8361
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%
-0.160 to 0.129
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.074
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.2461
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.087
Confidence Interval (2-Sided) 95%
-0.233 to 0.060
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.075
Estimation Comments Difference calculated as Tio R5 minus placebo
13.Secondary Outcome
Title Use of PRN Rescue Medication During the Night-time
Hide Description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12.

Measured values presented are actually adjusted means

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 126
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.285  (0.051) -0.250  (0.050) -0.310  (0.052)
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 0.6029
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%
-0.096 to 0.165
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.067
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.7034
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.026
Confidence Interval (2-Sided) 95%
-0.158 to 0.107
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.067
Estimation Comments Difference calculated as Tio R5 minus placebo
14.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 week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 126
Mean (Standard Error)
Unit of Measure: L/min
8.343  (3.613) 13.119  (3.500) 13.086  (3.630)
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 0.3083
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 4.776
Confidence Interval (2-Sided) 95%
-4.419 to 13.970
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.686
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.3179
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 4.743
Confidence Interval (2-Sided) 95%
-4.571 to 14.057
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.747
Estimation Comments Difference calculated as Tio R5 minus placebo
15.Secondary Outcome
Title Peak Expiratory Flow (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 week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: L/min
7.892  (3.717) 8.459  (3.599) 3.785  (3.731)
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 0.9061
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.567
Confidence Interval (2-Sided) 95%
-8.866 to 10.001
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.807
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.3990
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -4.107
Confidence Interval (2-Sided) 95%
-13.658 to 5.444
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.867
Estimation Comments Difference calculated as Tio R5 minus placebo
16.Secondary Outcome
Title Peak Expiratory Flow (PEF) Variability Change From Baseline
Hide Description

Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 125
Mean (Standard Error)
Unit of Measure: Percentage of PEF
0.150  (0.777) -0.800  (0.749) -0.352  (0.780)
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 0.3542
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.950
Confidence Interval (2-Sided) 95%
-2.959 to 1.060
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.025
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.6298
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.502
Confidence Interval (2-Sided) 95%
-2.545 to 1.541
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.042
Estimation Comments Difference calculated as Tio R5 minus placebo
17.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 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 126
Mean (Standard Error)
Unit of Measure: Litres
0.174  (0.030) 0.142  (0.029) 0.125  (0.030)
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 0.4066
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.032
Confidence Interval (2-Sided) 95%
-0.107 to 0.043
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.038
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.2032
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.049
Confidence Interval (2-Sided) 95%
-0.125 to 0.027
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.039
Estimation Comments Difference calculated as Tio R5 minus placebo
18.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 12.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Litres
0.155  (0.031) 0.104  (0.030) 0.094  (0.032)
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 0.2064
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.051
Confidence Interval (2-Sided) 95%
-0.131 to 0.028
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.041
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.1410
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%
-0.142 to 0.020
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.041
Estimation Comments Difference calculated as Tio R5 minus placebo
19.Secondary Outcome
Title Change From Baseline in Nighttime Awakenings
Hide Description

Change from baseline in nighttime awakenings based on the weekly mean at week 12.

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.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.165  (0.032) -0.166  (0.031) -0.159  (0.033)
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 0.9869
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.083 to 0.082
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.042
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.8730
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.007
Confidence Interval (2-Sided) 95%
-0.077 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.043
Estimation Comments Difference calculated as Tio R5 minus placebo
20.Secondary Outcome
Title Change From Baseline in Morning Asthma Symptoms
Hide Description

Change from baseline in morning asthma symptoms based on the weekly mean at week 12.

Morning asthma symptoms was assessed by the question "how were your asthma symptoms this morning?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.207  (0.038) -0.213  (0.037) -0.221  (0.038)
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 0.9043
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%
-0.103 to 0.091
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.049
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.7708
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%
-0.112 to 0.083
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.050
Estimation Comments Difference calculated as Tio R5 minus placebo
21.Secondary Outcome
Title Change From Baseline in Daytime Asthma Symptoms
Hide Description

Change from baseline in daytime asthma symptoms based on the weekly mean at week 12.

Daytime asthma symptoms was assessed by the question "how were your asthma symptoms during the day?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.226  (0.040) -0.262  (0.039) -0.239  (0.041)
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 0.4864
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.036
Confidence Interval (2-Sided) 95%
-0.139 to 0.066
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.052
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.7991
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.013
Confidence Interval (2-Sided) 95%
-0.117 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.053
Estimation Comments Difference calculated as Tio R5 minus placebo
22.Secondary Outcome
Title Change From Baseline in Daytime Activity Limitations
Hide Description

Change from baseline in daytime activity limitations based on the weekly mean at week 12.

Daytime activity limitations was assessed by the question "how limited were you in your activities today because of your asthma?" from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.210  (0.039) -0.203  (0.038) -0.222  (0.039)
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 0.8884
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.007
Confidence Interval (2-Sided) 95%
-0.092 to 0.106
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.050
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.8115
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.012
Confidence Interval (2-Sided) 95%
-0.112 to 0.088
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.051
Estimation Comments Difference calculated as Tio R5 minus placebo
23.Secondary Outcome
Title Change From Baseline in Daytime Experiences of Shortness of Breath
Hide Description

Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12.

Daytime experiences of shortness of breath was assessed by the question "how much shortness of breath did you experience during the day" from the e-diary. Scores range from 1 (none) to 5 (a very great deal).

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.204  (0.039) -0.187  (0.038) -0.287  (0.040)
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 0.7498
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.016
Confidence Interval (2-Sided) 95%
-0.084 to 0.117
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.051
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.1108
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated measures restricted maximum likelihood model
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.083
Confidence Interval (2-Sided) 95%
-0.185 to 0.019
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.052
Estimation Comments Difference calculated as Tio R5 minus placebo
24.Secondary Outcome
Title Change From Baseline in Daytime Experiences of Wheeze or Cough
Hide Description

Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12.

Daytime experiences of wheeze or cough was assessed by the question "did you experience wheeze or cough during the day?" from the e-diary. Scores range from 1 (not at all) to 5 (all the time).

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 127 136 126
Mean (Standard Error)
Unit of Measure: Units on a scale
-0.249  (0.045) -0.263  (0.044) -0.320  (0.046)
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 0.8055
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%
-0.131 to 0.102
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.059
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.2360
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%
-0.189 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.060
Estimation Comments Difference calculated as Tio R5 minus placebo
25.Secondary Outcome
Title Change From Baseline in Asthma Symptom-free Days
Hide Description

Change from baseline in asthma symptom-free days based on the weekly mean at week 12.

A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day.

Measured values presented are actually adjusted means.

Time Frame Baseline and 12 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 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 128 136 127
Mean (Standard Error)
Unit of Measure: Days
0.147  (0.031) 0.130  (0.030) 0.172  (0.031)
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 0.6748
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%
-0.097 to 0.063
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.041
Estimation Comments Difference calculated as Tio R2.5 minus placebo
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 0.5497
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%
-0.056 to 0.105
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.041
Estimation Comments Difference calculated as Tio R5 minus placebo
Time Frame From first drug intake until 30 days after last drug intake, up to 164 days
Adverse Event Reporting Description The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
 
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description Inhalation of placebo solution (2 puffs) once daily for 12 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 12 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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
All-Cause Mortality
Placebo Respimat Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Placebo Respimat Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/134 (1.49%)   2/136 (1.47%)   4/130 (3.08%) 
Infections and infestations       
Appendicitis  1  0/134 (0.00%)  0/136 (0.00%)  1/130 (0.77%) 
Nervous system disorders       
Epilepsy  1  0/134 (0.00%)  1/136 (0.74%)  0/130 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  1  1/134 (0.75%)  1/136 (0.74%)  3/130 (2.31%) 
Asthmatic crisis  1  1/134 (0.75%)  0/136 (0.00%)  0/130 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Respimat Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   49/134 (36.57%)   36/136 (26.47%)   35/130 (26.92%) 
Infections and infestations       
Nasopharyngitis  1  11/134 (8.21%)  6/136 (4.41%)  6/130 (4.62%) 
Investigations       
Peak expiratory flow rate decreased  1  20/134 (14.93%)  15/136 (11.03%)  15/130 (11.54%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  1  29/134 (21.64%)  20/136 (14.71%)  22/130 (16.92%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01634152    
Other Study ID Numbers: 205.446
2011-001777-43 ( EudraCT Number: EudraCT )
First Submitted: July 3, 2012
First Posted: July 6, 2012
Results First Submitted: November 17, 2015
Results First Posted: December 21, 2015
Last Update Posted: January 29, 2016