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Efficacy and Safety of 2 Doses of Tiotropium Via Respimat in Adult Patients With Mild 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: NCT01316380
Recruitment Status : Completed
First Posted : March 16, 2011
Results First Posted : July 31, 2013
Last Update Posted : April 15, 2015
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 2.5 mcg
Drug: tiotropium 5 mcg
Enrollment 465
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description Patients treated with matching placebo Patients treated with tiotropium inhalation solution 2.5 microgram qd Patients treated with tiotropium inhalation solution 5 microgram qd
Period Title: Overall Study
Started 156 154 155
Completed 154 149 152
Not Completed 2 5 3
Reason Not Completed
Adverse Event             0             2             1
Protocol Violation             0             0             1
Withdrawal by Subject             1             2             0
Other             0             1             1
Not treated             1             0             0
Arm/Group Title Placebo Tio R2.5 Tio R5 Total
Hide Arm/Group Description Patients treated with matching placebo Patients treated with tiotropium inhalation solution 2.5 microgram qd Patients treated with tiotropium inhalation solution 5 microgram qd Total of all reporting groups
Overall Number of Baseline Participants 155 154 155 464
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 155 participants 154 participants 155 participants 464 participants
42.8  (12.1) 43.8  (14.0) 41.9  (13.0) 42.9  (13)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 155 participants 154 participants 155 participants 464 participants
Female
103
  66.5%
82
  53.2%
96
  61.9%
281
  60.6%
Male
52
  33.5%
72
  46.8%
59
  38.1%
183
  39.4%
1.Primary Outcome
Title Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks.
Hide Description Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from Full Analysis Set (FAS) FAS is defined as all patients in the treated set who received at least one dose of randomized trial medication.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 151 152
Least Squares Mean (Standard Error)
Unit of Measure: Liter
0.134  (0.026) 0.293  (0.026) 0.262  (0.026)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments Step-wise testing for the two treatment groups for the primary endpoint, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.025 (one-sided) for primary endpoint.
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.128
Confidence Interval 95%
0.057 to 0.199
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Step-wise testing for the two treatment groups for the primary endpoint, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.025 (one-sided) for the primary endpoint.
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.159
Confidence Interval 95%
0.088 to 0.230
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
2.Secondary Outcome
Title Trough FEV1 Response Determined After a Treatment Period of 12 Weeks.
Hide Description The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 151 152
Least Squares Mean (Standard Error)
Unit of Measure: Liter
0.015  (0.026) 0.125  (0.026) 0.137  (0.027)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.122
Confidence Interval 95%
0.049 to 0.194
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.110
Confidence Interval 95%
0.038 to 0.182
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
3.Secondary Outcome
Title Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period.
Hide Description Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 151 152
Least Squares Mean (Standard Error)
Unit of Measure: Liter
0.126  (0.030) 0.231  (0.030) 0.183  (0.03)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1714
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.057
Confidence Interval 95%
-0.025 to 0.140
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.042
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0119
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.106
Confidence Interval 95%
0.023 to 0.188
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.042
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
4.Secondary Outcome
Title FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period.
Hide Description The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 151 152
Least Squares Mean (Standard Error)
Unit of Measure: Liter
0.048  (0.024) 0.198  (0.024) 0.174  (0.025)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.125
Confidence Interval 95%
0.058 to 0.192
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.149
Confidence Interval 95%
0.082 to 0.216
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
5.Secondary Outcome
Title FVC (AUC0-3h) Response at the End of the 12-week Treatment Period.
Hide Description The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 151 152
Least Squares Mean (Standard Error)
Unit of Measure: Liter
-0.000  (0.028) 0.101  (0.028) 0.061  (0.028)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1182
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.061
Confidence Interval 95%
-0.016 to 0.138
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.039
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0102
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.101
Confidence Interval 95%
0.024 to 0.178
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.039
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
6.Secondary Outcome
Title Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment
Hide Description For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline <= -0.5), no change (-0.5 <change from baseline < 0.5) and worsening (change from baseline >= 0.5).
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 154 149 152
Measure Type: Number
Unit of Measure: Number of patients
Responder 91 91 90
No change 61 48 57
Worsening 2 10 5
7.Secondary Outcome
Title Time to First Severe Asthma Exacerbation During the 12-week Treatment.
Hide Description Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 155 154 155
Median (Inter-Quartile Range)
Unit of Measure: Days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Since only 4 of the 155 patients in the placebo group, 6 of the 154 patients in the Tio R2.5 group and 1 of the 155 patients in the Tio R5 group had severe exacerbations, the median times were not calculable (nc).
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2155
Comments Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
Method Regression, Cox
Comments Parameter estimates of Cox proportional hazard model regarding. Only treatment was fitted as an effect in the model.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.25
Confidence Interval 95%
0.03 to 2.24
Estimation Comments If HR is below 1 then favours tiotropium.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5071
Comments Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
Method Regression, Cox
Comments Parameter estimates of Cox proportional hazard model regarding. Only treatment was fitted as an effect in the model.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.53
Confidence Interval 95%
0.43 to 5.44
Estimation Comments If HR is below 1 then favours tiotropium.
8.Secondary Outcome
Title Time to First Asthma Exacerbation During the 12-week Treatment.
Hide Description An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 155 154 155
Median (Inter-Quartile Range)
Unit of Measure: Days
NA [1] 
(87.0 to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Since 22 of the 155 in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group reported at least one asthma exacerbation, the median times were not calculable (nc).
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (nc).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1217
Comments Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
Method Regression, Cox
Comments Parameter estimates of Cox proportional hazard model regarding. Only treatment was fitted as an effect in the model.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval 95%
0.29 to 1.16
Estimation Comments If HR is below 1 then favours tiotropium.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (nc). The Hazard Ratio is still estimable from the Cox model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8974
Comments Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
Method Regression, Cox
Comments Parameter estimates of Cox proportional hazard model regarding. Only treatment was fitted as an effect in the model.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval 95%
0.53 to 1.75
Estimation Comments If HR is below 1 then favours tiotropium.
9.Secondary Outcome
Title Use of Rescue Medication During 24h Period
Hide Description

Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.

The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.

Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 153 150 152
Mean (Standard Error)
Unit of Measure: puffs of rescue medication
-0.815  (0.093) -0.594  (0.093) -0.848  (0.093)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0872
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.222
Confidence Interval (2-Sided) 95%
-0.032 to 0.476
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.129
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7995
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.033
Confidence Interval (2-Sided) 95%
-0.287 to 0.221
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.129
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
10.Secondary Outcome
Title Use of Rescue Medication During Daytime
Hide Description

Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.

The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.

Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 153 149 152
Mean (Standard Error)
Unit of Measure: puffs of rescue medication
-0.428  (0.055) -0.331  (0.055) -0.436  (0.055)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2038
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.097
Confidence Interval (2-Sided) 95%
-0.053 to 0.247
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.076
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9104
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.009
Confidence Interval (2-Sided) 95%
-0.158 to 0.141
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.076
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
11.Secondary Outcome
Title Use of Rescue Medication During Nighttime
Hide Description

Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.

The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.

Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 2.5 microgram qd
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 152 150 152
Mean (Standard Error)
Unit of Measure: puffs of rescue medication
-0.376  (0.049) -0.245  (0.049) -0.386  (0.049)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0559
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.131
Confidence Interval (2-Sided) 95%
-0.003 to 0.265
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.068
Estimation Comments Tio R2.5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Restricted maximum likelihood (REML)- based repeated measures model was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8795
Comments p-values serve an exploratory function only
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.010
Confidence Interval (2-Sided) 95%
-0.144 to 0.123
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.068
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
Time Frame 12 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Tio R2.5 Tio R5
Hide Arm/Group Description Enter description here, if needed Enter description here, if needed Enter description here, if needed
All-Cause Mortality
Placebo Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Placebo Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/155 (0.65%)   0/154 (0.00%)   1/155 (0.65%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Breast cancer in situ  0/155 (0.00%)  0/154 (0.00%)  1/155 (0.65%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  1/155 (0.65%)  0/154 (0.00%)  0/155 (0.00%) 
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Term from vocabulary, MedDRA 15.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Tio R2.5 Tio R5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   25/155 (16.13%)   30/154 (19.48%)   21/155 (13.55%) 
Investigations       
Peak expiratory flow rate decreased  6/155 (3.87%)  9/154 (5.84%)  6/155 (3.87%) 
Respiratory, thoracic and mediastinal disorders       
Asthma  19/155 (12.26%)  24/154 (15.58%)  17/155 (10.97%) 
1
Term from vocabulary, MedDRA 15.0
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.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Results Point of Contact
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: NCT01316380    
Other Study ID Numbers: 205.442
2010-023112-14 ( EudraCT Number: EudraCT )
First Submitted: March 15, 2011
First Posted: March 16, 2011
Results First Submitted: April 19, 2013
Results First Posted: July 31, 2013
Last Update Posted: April 15, 2015