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Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents 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: NCT01277523
Recruitment Status : Completed
First Posted : January 17, 2011
Results First Posted : October 20, 2014
Last Update Posted : October 20, 2014
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 high dose
Drug: placebo
Drug: tiotropium low dose
Enrollment 392
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Period Title: Overall Study
Started 135 127 130
Completed 132 126 130
Not Completed 3 1 0
Reason Not Completed
Adverse Event             1             0             0
Protocol Violation             2             0             0
Other Reason not Defined             0             1             0
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5 Total
Hide Arm/Group Description Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 5mcg tiotropium bromide solution 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 135 127 130 392
Hide Baseline Analysis Population Description
Treated set which included all randomised patients who were dispensed and received, at least one documented dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 135 participants 127 participants 130 participants 392 participants
14.1  (1.7) 14.4  (1.8) 14.3  (1.6) 14.2  (1.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 135 participants 127 participants 130 participants 392 participants
Female
56
  41.5%
47
  37.0%
47
  36.2%
150
  38.3%
Male
79
  58.5%
80
  63.0%
83
  63.8%
242
  61.7%
1.Primary Outcome
Title FEV1 peak0-3 Change From Baseline
Hide Description

Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: litres
0.438  (0.045) 0.550  (0.046) 0.528  (0.045)
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 0.0457
Comments Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.111
Confidence Interval (2-Sided) 95%
0.002 to 0.220
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.055
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 0.1039
Comments Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.090
Confidence Interval (2-Sided) 95%
-0.019 to 0.198
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.055
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
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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: litres
0.230  (0.048) 0.345  (0.048) 0.284  (0.048)
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 0.0509
Comments Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.115
Confidence Interval (2-Sided) 95%
-0.000 to 0.231
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 0.3605
Comments Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.054
Confidence Interval (2-Sided) 95%
-0.061 to 0.168
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.058
Estimation Comments Difference calculated as Tio R5 minus placebo
3.Secondary Outcome
Title FVC peak0-3 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 peak0-3h) 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
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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: Litres
0.279  (0.048) 0.370  (0.049) 0.342  (0.048)
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 0.1264
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.091
Confidence Interval (2-Sided) 95%
-0.026 to 0.207
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 0.2845
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.063
Confidence Interval (2-Sided) 95%
-0.053 to 0.179
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.059
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 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
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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: Litres
0.336  (0.043) 0.449  (0.043) 0.423  (0.043)
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 0.0338
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.113
Confidence Interval (2-Sided) 95%
0.009 to 0.217
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.053
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 0.0999
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.087
Confidence Interval (2-Sided) 95%
-0.017 to 0.191
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.053
Estimation Comments Difference calculated as Tio R5 minus placebo
5.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 AUC0-3h) 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
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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: litres
0.175  (0.045) 0.262  (0.047) 0.227  (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 0.1252
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.087
Confidence Interval (2-Sided) 95%
-0.024 to 0.198
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.057
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 0.3549
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.052
Confidence Interval (2-Sided) 95%
-0.058 to 0.163
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.056
Estimation Comments Difference calculated as Tio R5 minus placebo
6.Secondary Outcome
Title Control of Asthma as Assessed by ACQ6 Score.
Hide Description

Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12

The ACQ 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. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6.

The 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: units on a scale
1.144  (0.069) 1.262  (0.071) 1.197  (0.070)
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 0.1819
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.118
Confidence Interval (2-Sided) 95%
-0.055 to 0.292
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.088
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 0.5448
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.053
Confidence Interval (2-Sided) 95%
-0.119 to 0.226
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.088
Estimation Comments Difference calculated as Tio R5 minus placebo
7.Secondary Outcome
Title ACQ6 Score Responders
Hide Description

Responder rates based on the ACQ6 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).

The ACQ 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. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6.

No statistical testing was performed on ACQ6 responders.

Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

Full Analysis Set which included all randomised patients who were dispensed and received at least one documented dose of trial medication.

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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 135 127 130
Measure Type: Number
Unit of Measure: percentage of participants
Responder 74.1 74.0 74.6
No Change 23.7 19.7 23.1
Worsening 2.2 6.3 2.3
8.Secondary Outcome
Title Control of Asthma as Assessed by ACQ Total Score
Hide Description

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

The ACQ 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 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
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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 132 126 130
Mean (Standard Error)
Unit of Measure: units on a scale
1.234  (0.064) 1.292  (0.066) 1.270  (0.065)
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 0.4762
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.058
Confidence Interval (2-Sided) 95%
-0.102 to 0.219
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.082
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 0.6558
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.036
Confidence Interval (2-Sided) 95%
-0.123 to 0.196
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.081
Estimation Comments Difference calculated as Tio R5 minus placebo
9.Secondary Outcome
Title ACQ Total Score Responders
Hide Description

Responder rates based on the ACQ 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 total score responders.

The ACQ 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
Full Analysis Set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 135 127 130
Measure Type: Number
Unit of Measure: percentage of participants
Responder 73.3 74.8 73.1
No Change 23.7 22.0 26.2
Worsening 3.0 3.1 0.8
10.Secondary Outcome
Title Use of PRN Rescue Medication During the Day
Hide Description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the 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
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 was imputed by the available data from the patient. 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 131 124 130
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.482  (0.118) -0.483  (0.122) -0.540  (0.120)
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 0.9960
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.301 to 0.300
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.153
Estimation Comments [Not Specified]
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 0.7030
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.058
Confidence Interval (2-Sided) 95%
-0.355 to 0.239
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.151
Estimation Comments [Not Specified]
11.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
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 was imputed by the available data from the patient. 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 131 124 130
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.262  (0.073) -0.295  (0.075) -0.312  (0.073)
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 0.7309
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.032
Confidence Interval (2-Sided) 95%
-0.217 to 0.153
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.094
Estimation Comments [Not Specified]
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 0.5954
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.049
Confidence Interval (2-Sided) 95%
-0.232 to 0.133
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.093
Estimation Comments [Not Specified]
12.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
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 was imputed by the available data from the patient. 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 once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 131 124 129
Mean (Standard Error)
Unit of Measure: Number of puffs of rescue medication
-0.180  (0.064) -0.092  (0.066) -0.159  (0.065)
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 0.2841
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.089
Confidence Interval (2-Sided) 95%
-0.074 to 0.252
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.083
Estimation Comments [Not Specified]
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 0.7950
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.021
Confidence Interval (2-Sided) 95%
-0.140 to 0.182
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.082
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Time to First Severe Asthma Exacerbation During the 12-week Treatment Period.
Hide Description

Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values.

A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days.

Time Frame 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.
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description:
Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 135 127 130
Measure Type: Number
Unit of Measure: participants
1 1 2
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 0.9671
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.07 to 16.95
Estimation Comments [Not Specified]
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 0.5557
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.06
Confidence Interval (2-Sided) 95%
0.19 to 22.70
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period.
Hide Description Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values.
Time Frame 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.
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description:
Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 135 127 130
Measure Type: Number
Unit of Measure: participants
25 18 15
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 0.3567
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.41 to 1.38
Estimation Comments [Not Specified]
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 0.1168
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.32 to 1.14
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests
Hide Description Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events.
Time Frame From first drug administration until 30 days after last drug intake, up to 142 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set which included all randomised patients who were dispensed and received, at least one documented dose of trial medication.
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description:
Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
Overall Number of Participants Analyzed 135 127 130
Measure Type: Number
Unit of Measure: percentage of participants
Peak expiratory flow rate decreased 9.6 7.1 3.8
Blood glucose decreased 0.0 0.8 0.0
Time Frame From first drug administration until 30 days after last drug intake, up to 142 days
Adverse Event Reporting Description Treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication.
 
Arm/Group Title Placebo Respimat Tio R2.5 Tio R5
Hide Arm/Group Description Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. Inhalation of 5mcg tiotropium bromide solution 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   0/135 (0.00%)   1/127 (0.79%)   2/130 (1.54%) 
Infections and infestations       
Pyoderma  1  0/135 (0.00%)  1/127 (0.79%)  0/130 (0.00%) 
Injury, poisoning and procedural complications       
Ligament sprain  1  0/135 (0.00%)  0/127 (0.00%)  1/130 (0.77%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  1  0/135 (0.00%)  0/127 (0.00%)  1/130 (0.77%) 
Skin and subcutaneous tissue disorders       
Dermatitis atopic  1  0/135 (0.00%)  1/127 (0.79%)  0/130 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
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   23/135 (17.04%)   23/127 (18.11%)   16/130 (12.31%) 
Investigations       
Peak expiratory flow rate decreased  1  13/135 (9.63%)  9/127 (7.09%)  5/130 (3.85%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  1  14/135 (10.37%)  14/127 (11.02%)  14/130 (10.77%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
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 BIs intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01277523    
Other Study ID Numbers: 205.456
2010-021778-13 ( EudraCT Number: EudraCT )
First Submitted: January 13, 2011
First Posted: January 17, 2011
Results First Submitted: October 14, 2014
Results First Posted: October 20, 2014
Last Update Posted: October 20, 2014