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Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care (Study I)

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ClinicalTrials.gov Identifier: NCT00772538
Recruitment Status : Completed
First Posted : October 15, 2008
Results First Posted : September 27, 2012
Last Update Posted : August 18, 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 5mcg/day
Drug: placebo
Enrollment 459
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description Patients treated with matching placebo Patients treated with tiotropium inhalation solution 5 microgram qd
Period Title: Overall Study
Started 222 237
Completed 202 211
Not Completed 20 26
Reason Not Completed
Adverse Event             6             6
Protocol Violation             3             3
Lost to Follow-up             1             1
Withdrawal by Subject             3             8
Lack of Efficacy             0             1
Other             7             7
Arm/Group Title Placebo Tio R5 Total
Hide Arm/Group Description Patients treated with matching placebo Patients treated with tiotropium inhalation solution 5 microgram qd Total of all reporting groups
Overall Number of Baseline Participants 222 237 459
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 222 participants 237 participants 459 participants
53.9  (12.8) 52.9  (12.4) 53.4  (12.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 222 participants 237 participants 459 participants
Female
143
  64.4%
146
  61.6%
289
  63.0%
Male
79
  35.6%
91
  38.4%
170
  37.0%
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 24 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 24 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, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide 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 have baseline data and at least one on-treatment efficacy value.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.315  (0.026) 0.401  (0.025)
Show Statistical Analysis 1 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 0.0110
Comments Step-wise testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.05 (two-sided).
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 0.086
Confidence Interval 95%
0.020 to 0.152
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
2.Primary Outcome
Title Trough FEV1 Response Determined After a Treatment Period of 24 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 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.056  (0.025) 0.144  (0.024)
Show Statistical Analysis 1 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 0.0050
Comments Step-wise testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.088
Confidence Interval 95%
0.027 to 0.149
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
3.Primary Outcome
Title Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984).
Hide Description Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS of the pooled twin studies 205.416 and 205.417. As <50percent (149 of 454 patients in the placebo group and 122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 454 453
Median (Inter-Quartile Range)
Unit of Measure: Days
NA [1] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
As <50percent (149 of 454 patients in the placebo group) of patients had severe exacerbation, the median time was not calculable.
[2]
As <50percent (122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
Show Statistical Analysis 1 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 0.0343
Comments Confirmatory only if previous hypotheses for each of the 2 twin studies had been successful, significance level of alpha=0.05 (2-sided). A pre-specified interim analysis was performed. Cui et al (Biometrics,1999) was used to calculate the p-value.
Method Regression, Cox
Comments Parameter estimates of Cox proportional hazard model regression regarding. Only treatment was fitted as an effect in the model.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.790
Estimation Comments If HR is below 1 then favours tiotropium.
4.Secondary Outcome
Title Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-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 24 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, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.355  (0.033) 0.445  (0.032)
Show Statistical Analysis 1 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 0.0362
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.089
Confidence Interval 95%
0.006 to 0.173
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.043
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
5.Secondary Outcome
Title Trough FVC Response at the End of the 24-week Treatment Period.
Hide Description The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.022  (0.031) 0.157  (0.031)
Show Statistical Analysis 1 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 0.0007
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.136
Confidence Interval 95%
0.058 to 0.214
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.040
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
6.Secondary Outcome
Title FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-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 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.229  (0.024) 0.315  (0.024)
Show Statistical Analysis 1 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 0.0067
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.086
Confidence Interval 95%
0.024 to 0.149
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
7.Secondary Outcome
Title FVC (AUC0-3h) Response at the End of the 24-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 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.230  (0.031) 0.328  (0.030)
Show Statistical Analysis 1 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 0.0139
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.098
Confidence Interval 95%
0.020 to 0.176
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.040
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
8.Secondary Outcome
Title Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.
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 48 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, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.295  (0.026) 0.367  (0.026)
Show Statistical Analysis 1 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 0.0347
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.073
Confidence Interval 95%
0.005 to 0.140
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
9.Secondary Outcome
Title Trough FEV1 Response at the End of the 48-week Treatment Period.
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 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.087  (0.025) 0.129  (0.025)
Show Statistical Analysis 1 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 0.1896
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.042
Confidence Interval 95%
-0.021 to 0.104
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
10.Secondary Outcome
Title AUC0-3h FEV1 Response at the End of the 48-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 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.217  (0.025) 0.289  (0.024)
Show Statistical Analysis 1 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 0.0247
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.073
Confidence Interval 95%
0.009 to 0.136
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
11.Secondary Outcome
Title Peak FVC 0-3h Response at the End of the 48-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 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.337  (0.033) 0.462  (0.032)
Show Statistical Analysis 1 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 0.0039
Comments Significance level of alpha=0.05 (two-sided).
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%
0.040 to 0.210
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.043
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
12.Secondary Outcome
Title Trough FVC Response at the End of the 48-week Treatment Period.
Hide Description The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.062  (0.032) 0.173  (0.031)
Show Statistical Analysis 1 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 0.0063
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.111
Confidence Interval 95%
0.031 to 0.190
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.040
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
13.Secondary Outcome
Title FVC AUC0-3h Response at the End of the 48-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 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame Baseline and 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
0.223  (0.031) 0.344  (0.030)
Show Statistical Analysis 1 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 0.0027
Comments Significance level of alpha=0.05 (two-sided).
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%
0.042 to 0.201
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.041
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
14.Secondary Outcome
Title Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: L/min
-6.996  (3.754) 15.297  (3.602)
Show Statistical Analysis 1 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 <0.0001
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.293
Confidence Interval 95%
13.279 to 31.308
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.584
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
15.Secondary Outcome
Title Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: L/min
-3.865  (3.856) 19.402  (3.670)
Show Statistical Analysis 1 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 <0.0001
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 23.267
Confidence Interval 95%
14.027 to 32.507
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.699
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
16.Secondary Outcome
Title Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
-0.055  (0.023) 0.062  (0.022)
Show Statistical Analysis 1 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 <0.0001
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.117
Confidence Interval 95%
0.061 to 0.173
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
17.Secondary Outcome
Title Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Liter
-0.050  (0.024) 0.075  (0.023)
Show Statistical Analysis 1 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 <0.0001
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.124
Confidence Interval 95%
0.068 to 0.181
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
18.Secondary Outcome
Title Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Percent
-0.997  (0.602) -0.714  (0.578)
Show Statistical Analysis 1 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 0.7012
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.283
Confidence Interval 95%
-1.165 to 1.731
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.736
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
19.Secondary Outcome
Title Time to First Severe Asthma Exacerbation During the 48-week Treatment.
Hide Description Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS. As <50percent (68 of 222 patients in the placebo group and 53 of 237 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
20.Secondary Outcome
Title Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Hide Description Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS..
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
0 exacerbations 85 121
1 exacerbation 47 49
2 exacerbations 21 23
3 exacerbations 18 13
4 exacerbations 8 6
5 exacerbations 12 4
6 exacerbations 12 2
7-10 exacerbations 13 14
11-20 exacerbations 4 5
21+ exacerbations 2 0
Show Statistical Analysis 1 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 0.0102
Comments Significance level of alpha=0.05 (two-sided).
Method Poisson Regression
Comments Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.71
Confidence Interval 95%
0.55 to 0.92
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.09
Estimation Comments Tio R5 - Placebo
21.Secondary Outcome
Title Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Hide Description Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS..
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
0 exacerbations 154 184
1 exacerbation 39 37
2 exacerbations 15 10
3 exacerbations 5 3
4 exacerbations 6 0
5 exacerbations 2 2
6 exacerbations 1 0
7-10 exacerbations 0 1
Show Statistical Analysis 1 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 0.0062
Comments Significance level of alpha=0.05 (two-sided).
Method Poisson Regression
Comments Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.64
Confidence Interval 95%
0.46 to 0.88
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments Tio R5 - Placebo
22.Secondary Outcome
Title Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.
Hide Description Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
137 116
Show Statistical Analysis 1 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 0.0065
Comments Significance level of alpha=0.05 (two-sided).
Method Fisher Exact
Comments Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.59
Confidence Interval 95%
0.40 to 0.88
Estimation Comments Tio R5 vs Placebo
23.Secondary Outcome
Title Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.
Hide Description Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
68 53
Show Statistical Analysis 1 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 0.0561
Comments Significance level of alpha=0.05 (two-sided).
Method Fisher Exact
Comments Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.65
Confidence Interval 95%
0.42 to 1.01
Estimation Comments Tio R5 vs Placebo
24.Secondary Outcome
Title Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Hide Description Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS. As <50percent (10 of 222 patients in the placebo group and 8 of 237 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
25.Secondary Outcome
Title Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Hide Description [Not Specified]
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
0 hospitalisations 212 229
1 hospitalisations 9 6
2+ hospitalisations 1 2
Show Statistical Analysis 1 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 0.5538
Comments Significance level of alpha=0.05 (two-sided).
Method Poisson Regression
Comments Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.87
Confidence Interval 95%
0.54 to 1.39
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.21
Estimation Comments Tio R5 - Placebo
26.Secondary Outcome
Title Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Hide Description [Not Specified]
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Measure Type: Number
Unit of Measure: Participants
10 8
Show Statistical Analysis 1 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 0.6330
Comments Significance level of alpha=0.05 (two-sided).
Method Fisher Exact
Comments Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.74
Confidence Interval 95%
0.25 to 2.13
Estimation Comments Tio R5 vs Placebo
27.Secondary Outcome
Title Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.
Hide Description The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Scores on a scale
5.084  (0.059) 5.125  (0.057)
Show Statistical Analysis 1 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 0.5714
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.042
Confidence Interval 95%
-0.103 to 0.186
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.074
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
28.Secondary Outcome
Title AQLQ(S) Total Score at the End of the 48-week Treatment Period.
Hide Description The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Scores on a scale
5.109  (0.060) 5.147  (0.058)
Show Statistical Analysis 1 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 0.6099
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.038
Confidence Interval 95%
-0.109 to 0.185
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.075
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
29.Secondary Outcome
Title Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.
Hide Description For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Scores on a scale
2.120  (0.053) 1.995  (0.051)
Show Statistical Analysis 1 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 0.0586
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.126
Confidence Interval 95%
-0.256 to 0.005
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.066
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
30.Secondary Outcome
Title ACQ at the End of the 48-week Treatment Period.
Hide Description For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Scores on a scale
2.107  (0.054) 1.986  (0.052)
Show Statistical Analysis 1 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 0.0727
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.121
Confidence Interval 95%
-0.253 to 0.011
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.067
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
31.Secondary Outcome
Title Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Days
0.105  (0.020) 0.105  (0.019)
Show Statistical Analysis 1 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 0.9807
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.001
Confidence Interval 95%
-0.048 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
32.Secondary Outcome
Title Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .
Hide Description Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame Baseline and last 7 days before week 24 visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients from FAS.
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 222 237
Mean (Standard Error)
Unit of Measure: Puffs
-0.714  (0.140) -0.806  (0.135)
Show Statistical Analysis 1 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 0.5927
Comments Significance level of alpha=0.05 (two-sided).
Method Mixed Models Analysis
Comments REML-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.092
Confidence Interval 95%
-0.430 to 0.246
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.172
Estimation Comments Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
33.Post-Hoc Outcome
Title The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.417 (NCT00776984) and the Present 205.416 (NCT00772538)
Hide Description

The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at 24-weeks and 48-weeks (on combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.

The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

This outcome definition is taken from the primary outcome definition for the twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) of the same development program.

Time Frame 24 weeks, 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS of combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description:
Patients treated with matching placebo
Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed 454 453
Measure Type: Number
Unit of Measure: percentage of participants
24 weeks 46.9 53.9
48 weeks 45.2 58.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Comparison at 24 weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0427
Comments Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.32
Confidence Interval (2-Sided) 95%
1.01 to 1.73
Estimation Comments Tio R5 / Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5
Comments Comparison at 48 weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.68
Confidence Interval (2-Sided) 95%
1.28 to 2.21
Estimation Comments Tio R5 / Placebo
Time Frame 48 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Tio R5
Hide Arm/Group Description Patients treated with matching placebo Patients treated with tiotropium inhalation solution 5 μg qd
All-Cause Mortality
Placebo Tio R5
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Tio R5
Affected / at Risk (%) Affected / at Risk (%)
Total   15/222 (6.76%)   18/237 (7.59%) 
Cardiac disorders     
Arrhythmia supraventricular  1  0/222 (0.00%)  1/237 (0.42%) 
Atrial fibrillation  1  0/222 (0.00%)  1/237 (0.42%) 
Coronary artery occlusion  1  0/222 (0.00%)  1/237 (0.42%) 
Coronary artery stenosis  1  0/222 (0.00%)  1/237 (0.42%) 
Ventricular tachycardia  1  0/222 (0.00%)  1/237 (0.42%) 
Eye disorders     
Cataract  1  1/222 (0.45%)  0/237 (0.00%) 
Gastrointestinal disorders     
Abdominal discomfort  1  0/222 (0.00%)  1/237 (0.42%) 
Diverticulum  1  1/222 (0.45%)  0/237 (0.00%) 
Inguinal hernia  1  0/222 (0.00%)  1/237 (0.42%) 
Small intestinal obstruction  1  1/222 (0.45%)  0/237 (0.00%) 
General disorders     
Fat necrosis  1  0/222 (0.00%)  1/237 (0.42%) 
Infections and infestations     
Cellulitis  1  1/222 (0.45%)  0/237 (0.00%) 
Lobar pneumonia  1  0/222 (0.00%)  1/237 (0.42%) 
Pneumonia  1  0/222 (0.00%)  1/237 (0.42%) 
Injury, poisoning and procedural complications     
Burns first degree  1  0/222 (0.00%)  1/237 (0.42%) 
Fall  1  1/222 (0.45%)  0/237 (0.00%) 
Traumatic haematoma  1  1/222 (0.45%)  0/237 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/222 (0.00%)  1/237 (0.42%) 
Back disorder  1  0/222 (0.00%)  1/237 (0.42%) 
Bursitis  1  0/222 (0.00%)  1/237 (0.42%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Small cell lung cancer stage unspecified  1  0/222 (0.00%)  1/237 (0.42%) 
Nervous system disorders     
Cerebrovascular accident  1  0/222 (0.00%)  1/237 (0.42%) 
Paraesthesia  1  0/222 (0.00%)  1/237 (0.42%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  10/222 (4.50%)  9/237 (3.80%) 
Dyspnoea  1  0/222 (0.00%)  1/237 (0.42%) 
Hypoxia  1  0/222 (0.00%)  1/237 (0.42%) 
Sinus polyp  1  0/222 (0.00%)  1/237 (0.42%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Tio R5
Affected / at Risk (%) Affected / at Risk (%)
Total   148/222 (66.67%)   136/237 (57.38%) 
Infections and infestations     
Bronchitis  1  10/222 (4.50%)  12/237 (5.06%) 
Nasopharyngitis  1  20/222 (9.01%)  19/237 (8.02%) 
Upper respiratory tract infection  1  6/222 (2.70%)  13/237 (5.49%) 
Investigations     
Peak expiratory flow rate decreased  1  58/222 (26.13%)  49/237 (20.68%) 
Nervous system disorders     
Headache  1  13/222 (5.86%)  12/237 (5.06%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  99/222 (44.59%)  82/237 (34.60%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
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
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00772538     History of Changes
Other Study ID Numbers: 205.416
2008-001413-14 ( EudraCT Number: EudraCT )
First Submitted: October 13, 2008
First Posted: October 15, 2008
Results First Submitted: July 25, 2012
Results First Posted: September 27, 2012
Last Update Posted: August 18, 2014