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Tiotropium Respimat Pharmacokinetic Study in COPD

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ClinicalTrials.gov Identifier: NCT01222533
Recruitment Status : Completed
First Posted : October 18, 2010
Results First Posted : December 10, 2012
Last Update Posted : May 16, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: Tiotropium medium
Drug: Tiotropium low
Drug: Tiotropium high
Drug: Tiotropium 18mcg
Drug: Tiotropium placebo
Enrollment 154
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Study Overall
Hide Arm/Group Description Total number of patients randomised and treated in the study. This was a randomised 5-period crossover trial. 154 patients were randomised to one of 15 sequences and treated. The trial was blinded within the 4 Respimat treatments, but open for the HandiHaler treatment. Each of the 5 treatment regimens was taken for 4 weeks without washouts between treatment periods.
Period Title: Overall Study
Started 154 [1]
Received Placebo 147
Received Tio R1.25 147
Received Tio R2.5 145
Received Tio R5 150
Received Tio HH18 146
Completed 140 [2]
Not Completed 14
Reason Not Completed
Adverse Event             5
Withdrawal by Subject             5
Other             4
[1]
Entered and treated.
[2]
Completed planned observation time (week 21)
Arm/Group Title Study Overall
Hide Arm/Group Description Total number of patients randomised and treated in the study.
Overall Number of Baseline Participants 154
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 154 participants
63.1  (7.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 154 participants
Female
37
  24.0%
Male
117
  76.0%
1.Primary Outcome
Title Maximum Plasma Concentration at Steady-state (Cmax,ss)
Hide Description Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Set. This analysis set includes all patients in the treated set who had at least one blood sample drawn or one urine sample collected for PK analysis. Patients with an important protocol violation relevant to the PK population were excluded. No PK data for placebo. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 104 110 113 113
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/ml
2.81
(53.0%)
5.07
(61.8%)
10.5
(66.4%)
12.9
(64.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R5, Tio HH18
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The standard bioequivalence range of 80 to 125% was pre-specified for Cmax,ss in order to assess the relative systemic exposure following inhalation of Tio R5 compared to Tio HH18. Bioequivalence was not used as a surrogate for efficacy.
Statistical Test of Hypothesis P-Value 0.4423
Comments Maximum of two one-sided p-values for geometric mean ratio being outside interval 80 percent to 125 percent.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio (percentage)
Estimated Value 80.66
Confidence Interval 90%
73.49 to 88.52
Parameter Dispersion
Type: Standard Deviation
Value: 43.4
Estimation Comments Standard deviation is actually the geometric coefficient of variation.
2.Primary Outcome
Title Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss)
Hide Description AUC0-6h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 6 hours post-dose at steady-state. AUC0-6h,ss was calculated using the linear up/log down algorithm.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. No PK data for Placebo. The low number of non-missing AUC0-6h,ss results for the Tio R 1.25 and Tio R 2.5 cohorts is due to the exclusion of results below the limit of quantification.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 22 76 107 113
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg*h/ml
10.0
(25.3%)
12.8
(29.9%)
22.1
(47.8%)
28.4
(52.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R5, Tio HH18
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The standard bioequivalence range of 80 to 125% was pre-specified for AUC0-6,ss in order to assess the relative systemic exposure following inhalation of Tio R5 compared to Tio HH18. Bioequivalence was not used as a surrogate for efficacy.
Statistical Test of Hypothesis P-Value 0.8683
Comments Maximum of two one-sided p-values for geometric mean ratio being outside interval 80 percent to 125 percent.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio (percentage)
Estimated Value 75.99
Confidence Interval 90%
70.44 to 81.98
Parameter Dispersion
Type: Standard Deviation
Value: 34.1
Estimation Comments Standard deviation is actually the geometric coefficient of variation.
3.Secondary Outcome
Title Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period
Hide Description Defined as FEV1 measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) with imputed data. FAS includes all patients in the treated set who have analysable data for at least one efficacy endpoint during the relevant crossover period.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 143 143 144 143 142
Mean (Standard Error)
Unit of Measure: Liter
1.345  (0.045) 1.432  (0.045) 1.446  (0.045) 1.466  (0.045) 1.473  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.087
Confidence Interval 95%
0.060 to 0.114
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments Tio R1.25-Placebo
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.101
Confidence Interval 95%
0.074 to 0.128
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.121
Confidence Interval 95%
0.094 to 0.148
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments Tio R5-Placebo
4.Secondary Outcome
Title FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period
Hide Description FEV1 AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 143 143 144 143 142
Mean (Standard Error)
Unit of Measure: Liter
1.371  (0.046) 1.535  (0.046) 1.556  (0.046) 1.562  (0.046) 1.567  (0.046)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.165
Confidence Interval 95%
0.141 to 0.189
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments Tio R1.25-Placebo.
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.185
Confidence Interval 95%
0.161 to 0.209
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.191
Confidence Interval 95%
0.167 to 0.216
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments Tio R5-Placebo
5.Secondary Outcome
Title FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period
Hide Description FEV1 AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 143 143 144 143 142
Mean (Standard Error)
Unit of Measure: Liter
1.366  (0.046) 1.521  (0.046) 1.546  (0.046) 1.553  (0.046) 1.558  (0.046)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.155
Confidence Interval 95%
0.130 to 0.180
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments Tio R1.25-Placebo
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.180
Confidence Interval 95%
0.155 to 0.205
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.187
Confidence Interval 95%
0.162 to 0.211
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments Tio R5-Placebo
6.Secondary Outcome
Title Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period
Hide Description Defined as the pre-dose FVC measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 142 143 143 143 142
Mean (Standard Error)
Unit of Measure: Liter
3.116  (0.077) 3.254  (0.077) 3.304  (0.077) 3.352  (0.077) 3.351  (0.077)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.138
Confidence Interval 95%
0.083 to 0.194
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Tio R1.25-Placebo
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.188
Confidence Interval 95%
0.133 to 0.244
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.236
Confidence Interval 95%
0.180 to 0.292
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Tio R5-Placebo
7.Secondary Outcome
Title FVC AUC0-6h at the End of Each Treatment Period
Hide Description FVC AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 142 143 143 143 142
Mean (Standard Error)
Unit of Measure: Liter
3.153  (0.079) 3.436  (0.078) 3.472  (0.078) 3.488  (0.078) 3.483  (0.079)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.283
Confidence Interval 95%
0.241 to 0.326
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.022
Estimation Comments Tio R1.25-Placebo
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.319
Confidence Interval 95%
0.276 to 0.362
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.022
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.335
Confidence Interval 95%
0.292 to 0.378
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.022
Estimation Comments Tio R5-Placebo
8.Secondary Outcome
Title FVC AUC0-3h at the End of Each Treatment Period
Hide Description FVC AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 142 143 143 143 142
Mean (Standard Error)
Unit of Measure: Liter
3.140  (0.078) 3.421  (0.078) 3.465  (0.078) 3.479  (0.078) 3.480  (0.078)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R1.25
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.281
Confidence Interval 95%
0.236 to 0.325
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R1.25-Placebo
Show Statistical Analysis 2 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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.324
Confidence Interval 95%
0.279 to 0.369
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R2.5-Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
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 [Not Specified]
Method ANOVA
Comments Adjusted for sequence, patients within sequences, period and treatment.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.339
Confidence Interval 95%
0.294 to 0.384
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R5-Placebo
9.Secondary Outcome
Title FEV1 at Each Planned Time at the End of Each Treatment Period
Hide Description Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 143 143 144 143 142
Mean (Standard Error)
Unit of Measure: Liter
Timepoint 0:00 (trough) 1.349  (0.045) 1.436  (0.045) 1.450  (0.045) 1.470  (0.045) 1.477  (0.045)
Timepoint 0:30 1.366  (0.046) 1.501  (0.046) 1.522  (0.046) 1.541  (0.046) 1.554  (0.046)
Timepoint 1:00 1.371  (0.046) 1.529  (0.046) 1.552  (0.046) 1.560  (0.046) 1.571  (0.046)
Timepoint 2:00 1.375  (0.046) 1.543  (0.046) 1.573  (0.046) 1.572  (0.046) 1.571  (0.046)
Timepoint 3:00 1.375  (0.047) 1.556  (0.047) 1.582  (0.047) 1.584  (0.047) 1.580  (0.047)
Timepoint 4:00 1.374  (0.047) 1.557  (0.047) 1.575  (0.047) 1.578  (0.047) 1.582  (0.047)
Timepoint 5:00 1.394  (0.047) 1.562  (0.047) 1.571  (0.047) 1.579  (0.047) 1.588  (0.047)
Timepoint 6:00 1.375  (0.047) 1.536  (0.048) 1.551  (0.047) 1.558  (0.047) 1.570  (0.048)
10.Secondary Outcome
Title FVC at Each Planned Time at the End of Each Treatment Period
Hide Description Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
Time Frame 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 142 143 143 143 142
Mean (Standard Error)
Unit of Measure: Liter
Timepoint 0:00 (trough) 3.118  (0.076) 3.255  (0.076) 3.307  (0.076) 3.356  (0.076) 3.351  (0.076)
Timepoint 0:30 3.131  (0.077) 3.390  (0.077) 3.435  (0.077) 3.473  (0.077) 3.496  (0.077)
Timepoint 1:00 3.152  (0.078) 3.449  (0.078) 3.484  (0.078) 3.488  (0.078) 3.499  (0.078)
Timepoint 2:00 3.146  (0.078) 3.443  (0.078) 3.489  (0.078) 3.499  (0.078) 3.487  (0.078)
Timepoint 3:00 3.156  (0.078) 3.466  (0.078) 3.513  (0.078) 3.516  (0.078) 3.497  (0.078)
Timepoint 4:00 3.161  (0.079) 3.468  (0.079) 3.495  (0.079) 3.505  (0.079) 3.501  (0.079)
Timepoint 5:00 3.191  (0.079) 3.459  (0.079) 3.467  (0.079) 3.501  (0.079) 3.488  (0.079)
Timepoint 6:00 3.168  (0.079) 3.417  (0.079) 3.470  (0.079) 3.473  (0.079) 3.469  (0.079)
11.Secondary Outcome
Title Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss)
Hide Description AUC0-1h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 1 hour post-dose at steady-state. AUC0-1h,ss was calculated using the linear up/log down algorithm.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 61 97 112 113
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg*h/mL
2.08
(32.3%)
3.16
(44.4%)
6.13
(58.3%)
7.79
(54.9%)
12.Secondary Outcome
Title Time to Maximum Plasma Concentration at Steady-state (Tmax,ss)
Hide Description Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 104 110 113 113
Median (Full Range)
Unit of Measure: hours
0.100
(0.0330 to 2.00)
0.0830
(0.0330 to 6.00)
0.117
(0.0330 to 0.333)
0.117
(0.0330 to 1.00)
13.Secondary Outcome
Title Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss)
Hide Description Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state.
Time Frame Based on urine sampling for PK assessments done at 4 weeks in the following intervals: -1 to 0 hour (h), 0 to 2 h and 2 to 6 h post-dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 108 110 107 109
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng
88.7
(68.0%)
177
(68.0%)
387
(65.9%)
522
(53.8%)
14.Secondary Outcome
Title Pre-dose Plasma Concentration at Steady-state (Cpre,ss)
Hide Description Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time point: 5 minutes (min) before first dosing of study drug (baseline)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 5 19 74 85
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
1.57
(43.1%)
1.39
(22.8%)
1.60
(35.8%)
1.71
(42.5%)
15.Secondary Outcome
Title Renal Clearance at Steady-state (CL R,0-6h,ss)
Hide Description Renal clearance of the drug over the time interval 0 to 6 hours at steady-state. CL R,0-6h,ss was calculated as the quotient of Ae0-6h,ss and AUC0-6h,ss.
Time Frame Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 22 75 102 109
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mL/min
256
(32.1%)
277
(55.8%)
307
(39.6%)
310
(40.4%)
16.Secondary Outcome
Title Minimum Plasma Concentration at Steady-state (Cmin,ss)
Hide Description Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.
Time Frame Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Set. All patients with analysable data.
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 0 103 110 113 113
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
1.16
(14.5%)
1.25
(17.7%)
1.57
(32.3%)
1.76
(42.3%)
17.Other Pre-specified Outcome
Title Maximum Heart Rate (HR)
Hide Description Maximum HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded).
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Mean (Standard Deviation)
Unit of Measure: bpm
Day 29 6.5 h(N=115,115,115,116,113) 109.29  (15.23) 109.57  (15.29) 109.93  (15.47) 109.34  (14.36) 108.68  (14.28)
Day 29 1st h(N=114,113,115,115,111) 97.83  (13.65) 99.20  (14.65) 98.43  (14.68) 97.16  (13.97) 97.33  (13.00)
Day 26 6.5 h(N=115,110,113,110,112) 108.35  (16.32) 107.37  (14.04) 108.90  (15.85) 107.65  (16.37) 109.57  (14.70)
Day 26 1st h(N=115,109,113,107,109) 91.73  (12.44) 91.51  (12.87) 92.59  (15.40) 91.60  (12.07) 92.74  (12.75)
18.Other Pre-specified Outcome
Title Mean Heart Rate (HR)
Hide Description Mean HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Mean (Standard Deviation)
Unit of Measure: bpm
Day 29 6.5 h(N=115,115,115,116,113) 76.97  (10.39) 76.37  (10.69) 77.75  (10.95) 76.87  (10.82) 77.31  (10.45)
Day 29 1st h(N=114,113,115,115,111) 73.87  (10.07) 73.76  (10.60) 74.39  (10.82) 73.82  (11.06) 73.71  (9.80)
Day 26 6.5 h(N=115,110,113,110,112) 75.76  (10.88) 75.00  (10.87) 76.25  (12.00) 75.35  (10.86) 75.81  (10.39)
Day 26 1st h(N=115,109,113,107,109) 70.75  (10.20) 70.33  (10.66) 71.11  (11.93) 70.67  (10.77) 70.21  (9.58)
19.Other Pre-specified Outcome
Title SVPB Total
Hide Description The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 109 112 109 108 107
Day 29 1st h 83 79 75 84 75
Day 26 6.5 h 111 103 106 98 105
Day 26 1st h 82 74 75 62 66
20.Other Pre-specified Outcome
Title SVPB Runs
Hide Description The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 47 36 44 34 39
Day 29 1st h 9 16 8 5 6
Day 26 6.5 h 35 34 29 36 34
Day 26 1st h 12 6 9 11 10
21.Other Pre-specified Outcome
Title SVPB Pairs
Hide Description The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 48 52 55 49 53
Day 29 1st h 17 20 19 20 16
Day 26 6.5 h 41 46 29 42 45
Day 26 1st h 18 13 10 14 13
22.Other Pre-specified Outcome
Title SVPB Singles
Hide Description The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 109 112 109 108 107
Day 29 1st h 82 77 72 82 73
Day 26 6.5 h 111 102 106 98 105
Day 26 1st h 78 74 74 61 64
23.Other Pre-specified Outcome
Title VPB Total
Hide Description The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 91 99 90 96 96
Day 29 1st h 59 63 58 50 59
Day 26 6.5 h 92 82 83 89 88
Day 26 1st h 59 49 49 49 56
24.Other Pre-specified Outcome
Title VPB Runs
Hide Description The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 3 5 4 10 9
Day 29 1st h 0 3 2 2 1
Day 26 6.5 h 8 7 8 9 9
Day 26 1st h 0 2 1 4 3
25.Other Pre-specified Outcome
Title VPB Pairs
Hide Description The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 24 19 21 16 22
Day 29 1st h 8 6 6 6 7
Day 26 6.5 h 24 20 19 21 22
Day 26 1st h 7 10 7 6 10
26.Other Pre-specified Outcome
Title VPB Singles
Hide Description The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.
Time Frame 6.5 hours (including pre dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description:
Matching Placebo once daily (qd) delivered by the Respimat inhaler
Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning
Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning
Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Overall Number of Participants Analyzed 115 115 115 116 113
Measure Type: Number
Unit of Measure: participants
Day 29 6.5 h 91 99 89 94 96
Day 29 1st h 59 63 58 50 58
Day 26 6.5 h 92 82 81 88 88
Day 26 1st h 59 49 48 49 55
Time Frame 4 weeks + 30 days if in last period
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Hide Arm/Group Description Matching Placebo once daily (qd) delivered by the Respimat inhaler Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
All-Cause Mortality
Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/147 (2.04%)   2/147 (1.36%)   0/145 (0.00%)   3/150 (2.00%)   2/146 (1.37%) 
Gastrointestinal disorders           
Colitis ischaemic  0/147 (0.00%)  0/147 (0.00%)  0/145 (0.00%)  1/150 (0.67%)  0/146 (0.00%) 
Haemorrhoidal haemorrhage  1/147 (0.68%)  0/147 (0.00%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Pancreatitis  0/147 (0.00%)  0/147 (0.00%)  0/145 (0.00%)  1/150 (0.67%)  0/146 (0.00%) 
Infections and infestations           
Infective exacerbation of chronic obstructive airways disease  1/147 (0.68%)  0/147 (0.00%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Pneumonia  0/147 (0.00%)  0/147 (0.00%)  0/145 (0.00%)  0/150 (0.00%)  1/146 (0.68%) 
Injury, poisoning and procedural complications           
Tendon rupture  1/147 (0.68%)  0/147 (0.00%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Musculoskeletal and connective tissue disorders           
Spinal column stenosis  0/147 (0.00%)  1/147 (0.68%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Prostate cancer  0/147 (0.00%)  1/147 (0.68%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Nervous system disorders           
Cerebrovascular accident  0/147 (0.00%)  1/147 (0.68%)  0/145 (0.00%)  0/150 (0.00%)  0/146 (0.00%) 
Renal and urinary disorders           
Azotaemia  0/147 (0.00%)  0/147 (0.00%)  0/145 (0.00%)  1/150 (0.67%)  0/146 (0.00%) 
Renal tubular necrosis  0/147 (0.00%)  0/147 (0.00%)  0/145 (0.00%)  1/150 (0.67%)  0/146 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Chronic obstructive pulmonary disease  1/147 (0.68%)  0/147 (0.00%)  0/145 (0.00%)  0/150 (0.00%)  1/146 (0.68%) 
1
Term from vocabulary, MEDDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Tio R1.25 Tio R2.5 Tio R5 Tio HH18
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   20/147 (13.61%)   11/147 (7.48%)   4/145 (2.76%)   16/150 (10.67%)   10/146 (6.85%) 
Infections and infestations           
Nasopharyngitis  1  6/147 (4.08%)  9/147 (6.12%)  2/145 (1.38%)  14/150 (9.33%)  7/146 (4.79%) 
Respiratory, thoracic and mediastinal disorders           
Dyspnoea  1  14/147 (9.52%)  5/147 (3.40%)  2/145 (1.38%)  3/150 (2.00%)  3/146 (2.05%) 
Indicates events were collected by systematic assessment
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
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: NCT01222533     History of Changes
Other Study ID Numbers: 205.458
2009-016251-21 ( EudraCT Number: EudraCT )
First Submitted: October 15, 2010
First Posted: October 18, 2010
Results First Submitted: November 13, 2012
Results First Posted: December 10, 2012
Last Update Posted: May 16, 2014