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Trial record 21 of 10795 for:    Placebo AND once

A Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for Four Weeks in Patients With Moderate Persistent Asthma

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ClinicalTrials.gov Identifier: NCT01152450
Recruitment Status : Completed
First Posted : June 29, 2010
Results First Posted : October 30, 2012
Last Update Posted : May 16, 2014
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Asthma
Interventions Drug: Tiotropium 2.5 µg b.i.d
Drug: Placebo
Drug: Tiotropium 5 µg q.d.
Enrollment 94
Recruitment Details A total of 94 patients entered the study and was treated whilst 89 patients completed the trial.
Pre-assignment Details Randomised, double-blind, placebo controlled, cross-over design without washout phase between the three periods. Patients were randomized equally to one of the six sequences (ABC, ACB, BAC, BCA, CAB, CBA).
Arm/Group Title Tio R2.5 Twice Daily (Bid) /Tio R5 Once Daily (qd) /Placebo Tio R2.5 Bid/Placebo/Tio R5 qd Tio R5 qd/Tio R2.5 Bid/Placebo Tio R5 qd/Placebo/Tio R2.5 Bid Placebo/Tio R2.5 Bid/Tio R5 qd Placebo/Tio R5 qd/Tio R2.5 Bid
Hide Arm/Group Description Patients treated with Tiotropium 2.5 mcg in period 1 (morning and evening), with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 2 and with a matching Placebo in period 3 (morning and evening). All products were delivered by the Respimat inhaler, on top on maintenance therapy with inhaled corticosteroid (iCS). No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks. Patients treated with Tiotropium 2.5 mcg in period 1 (morning and evening), with a matching Placebo in period 2 (morning and evening) and with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 3. All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks. Patients treated with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 1, with Tiotropium 2.5 mcg in period 2 (morning and evening) and with matching Placebo in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks. Patients treated with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 1, with matching Placebo in period 2 (morning and evening) and with Tiotropium 2.5 mcg in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks. Patients treated with matching Placebo in period 1 (morning and evening), with Tiotropium 2.5 mcg in period 2 (morning and evening) and with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 3. All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks. Patients treated with a matching Placebo in period 1 (morning and evening), with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 2 and with Tiotropium 2.5 mcg in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.
Period Title: Period 1 (4 Weeks)
Started 15 16 17 15 18 13
Completed 15 15 16 15 16 12
Not Completed 0 1 1 0 2 1
Reason Not Completed
Adverse Event             0             0             0             0             1             1
Protocol Violation             0             0             0             0             1             0
Lost to Follow-up             0             1             1             0             0             0
Period Title: Period 2 (4 Weeks)
Started 15 15 16 15 16 12
Completed 15 15 16 15 16 12
Not Completed 0 0 0 0 0 0
Period Title: Period 3 (4 Weeks)
Started 15 15 16 15 16 12
Completed 15 15 16 15 16 12
Not Completed 0 0 0 0 0 0
Arm/Group Title Baseline Total
Hide Arm/Group Description Total number of patients randomised and treated in the study.
Overall Number of Baseline Participants 94
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 94 participants
44.3  (13.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants
Female
55
  58.5%
Male
39
  41.5%
1.Primary Outcome
Title Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response
Hide Description Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time Frame 10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) defined as all treated patients who had baseline data and at least 1 on-treatment efficacy measurement after 4 weeks on treatment within a period.
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.091  (0.043) 0.241  (0.044) 0.250  (0.044)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.149
Confidence Interval 95%
0.102 to 0.196
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.158
Confidence Interval 95%
0.111 to 0.205
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.009
Confidence Interval 95%
-0.038 to 0.056
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R5 qd - Tio R2.5 bid
2.Secondary Outcome
Title Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time Frame Baseline and during week 4 of each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 88
Mean (Standard Error)
Unit of Measure: L/min
1.953  (5.864) 23.281  (5.907) 24.310  (5.924)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 21.328
Confidence Interval 95%
11.084 to 31.573
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.190
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.357
Confidence Interval 95%
12.044 to 32.670
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.225
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.029
Confidence Interval 95%
-9.318 to 11.376
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.242
Estimation Comments Tio R5 qd - Tio R2.5 bid
3.Secondary Outcome
Title Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time Frame Baseline and during week 4 of each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 89
Mean (Standard Error)
Unit of Measure: L/min
-1.560  (5.891) 28.360  (5.932) 27.096  (5.931)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 29.920
Confidence Interval 95%
20.001 to 39.839
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.026
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 28.657
Confidence Interval 95%
18.707 to 38.606
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.042
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.264
Confidence Interval 95%
-11.243 to 8.716
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.056
Estimation Comments Tio R5 qd - Tio R2.5 bid
4.Secondary Outcome
Title FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.048  (0.044) 0.217  (0.044) 0.233  (0.044)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.169
Confidence Interval 95%
0.120 to 0.218
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.185
Confidence Interval 95%
0.136 to 0.234
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.016
Confidence Interval 95%
-0.033 to 0.065
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Tio R5 qd - Tio R2.5 bid
5.Secondary Outcome
Title FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.135  (0.044) 0.264  (0.045) 0.266  (0.044)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.129
Confidence Interval 95%
0.077 to 0.181
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.131
Confidence Interval 95%
0.079 to 0.183
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.002
Confidence Interval 95%
-0.050 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R5 qd - Tio R2.5 bid
6.Secondary Outcome
Title Peak FEV1 Within 24 Hours Post-dose Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.337  (0.045) 0.469  (0.045) 0.468  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.132
Confidence Interval 95%
0.084 to 0.179
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.131
Confidence Interval 95%
0.084 to 0.179
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.000
Confidence Interval 95%
-0.048 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.024
Estimation Comments Tio R5 qd - Tio R2.5 bid
7.Secondary Outcome
Title Trough FEV1 Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.143  (0.044) 0.254  (0.044) 0.275  (0.044)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.111
Confidence Interval 95%
0.053 to 0.170
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.133
Confidence Interval 95%
0.074 to 0.191
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.021
Confidence Interval 95%
-0.037 to 0.080
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Tio R5 qd - Tio R2.5 bid
8.Secondary Outcome
Title Trough Forced Vital Capacity (FVC) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.112  (0.046) 0.179  (0.046) 0.168  (0.046)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0515
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.068
Confidence Interval 95%
0.000 to 0.136
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1058
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.056
Confidence Interval 95%
-0.012 to 0.124
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.012
Confidence Interval 95%
-0.080 to 0.057
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Tio R5 qd - Tio R2.5 bid
9.Secondary Outcome
Title FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
-0.026  (0.046) 0.099  (0.046) 0.074  (0.046)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.125
Confidence Interval 95%
0.073 to 0.177
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.100
Confidence Interval 95%
0.048 to 0.152
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.025
Confidence Interval 95%
-0.077 to 0.027
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R5 qd - Tio R2.5 bid
10.Secondary Outcome
Title FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.032  (0.045) 0.108  (0.045) 0.100  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0051
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.076
Confidence Interval 95%
0.023 to 0.129
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0123
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.068
Confidence Interval 95%
0.015 to 0.120
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.008
Confidence Interval 95%
-0.061 to 0.045
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R5 qd - Tio R2.5 bid
11.Secondary Outcome
Title Peak FVC Within 24 Hours Post-dose Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.302  (0.045) 0.380  (0.045) 0.350  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0042
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.077
Confidence Interval 95%
0.025 to 0.130
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0747
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.048
Confidence Interval 95%
-0.005 to 0.100
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.029
Confidence Interval 95%
-0.082 to 0.023
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio R5 qd - Tio R2.5 bid
12.Secondary Outcome
Title Individual FEV1 Over Time (at Each Timepoint at Visits) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
Timepoint -0:10 (hours:minutes) 0.143  (0.044) 0.254  (0.044) 0.275  (0.044)
Timepoint 0:30 (hours:minutes) 0.132  (0.044) 0.281  (0.044) 0.304  (0.044)
Timepoint 1:00 (hours:minutes) 0.123  (0.044) 0.274  (0.044) 0.289  (0.044)
Timepoint 2:00 (hours:minutes) 0.103  (0.044) 0.270  (0.044) 0.297  (0.044)
Timepoint 3:00 (hours:minutes) 0.082  (0.044) 0.264  (0.044) 0.268  (0.044)
Timepoint 4:00 (hours:minutes) 0.062  (0.045) 0.248  (0.045) 0.263  (0.045)
Timepoint 11:50 (hours:minutes) -0.021  (0.049) 0.134  (0.049) 0.150  (0.049)
Timepoint 12:30 (hours:minutes) 0.075  (0.047) 0.198  (0.047) 0.217  (0.047)
Timepoint 13:00 (hours:minutes) 0.101  (0.047) 0.250  (0.047) 0.237  (0.047)
Timepoint 14:00 (hours:minutes) 0.138  (0.045) 0.288  (0.045) 0.282  (0.045)
Timepoint 15:00 (hours:minutes) 0.163  (0.046) 0.299  (0.046) 0.308  (0.046)
Timepoint 16:00 (hours:minutes) 0.161  (0.046) 0.306  (0.046) 0.313  (0.046)
Timepoint 18:00 (hours:minutes) 0.177  (0.047) 0.300  (0.047) 0.308  (0.047)
Timepoint 20:00 (hours:minutes) 0.127  (0.045) 0.256  (0.046) 0.245  (0.045)
Timepoint 22:00 (hours:minutes) 0.117  (0.047) 0.221  (0.047) 0.244  (0.047)
Timepoint 23:00 (hours:minutes) 0.124  (0.045) 0.243  (0.045) 0.223  (0.045)
Timepoint 23:50 (hours:minutes) 0.125  (0.047) 0.232  (0.047) 0.224  (0.047)
13.Secondary Outcome
Title Individual FVC Over Time (at Each Timepoint at Visits) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
Timepoint -0:10 (hours:minutes) 0.112  (0.046) 0.179  (0.046) 0.168  (0.046)
Timepoint 0:30 (hours:minutes) 0.053  (0.047) 0.158  (0.048) 0.130  (0.047)
Timepoint 1:00 (hours:minutes) 0.055  (0.047) 0.152  (0.047) 0.124  (0.047)
Timepoint 2:00 (hours:minutes) 0.033  (0.047) 0.131  (0.047) 0.093  (0.047)
Timepoint 3:00 (hours:minutes) -0.003  (0.047) 0.100  (0.047) 0.057  (0.047)
Timepoint 4:00 (hours:minutes) -0.040  (0.049) 0.096  (0.049) 0.065  (0.049)
Timepoint 11:50 (hours:minutes) -0.064  (0.049) 0.070  (0.049) 0.060  (0.049)
Timepoint 12:30 (hours:minutes) 0.004  (0.046) 0.133  (0.046) 0.103  (0.046)
Timepoint 13:00 (hours:minutes) 0.010  (0.047) 0.114  (0.047) 0.102  (0.047)
Timepoint 14:00 (hours:minutes) 0.038  (0.047) 0.106  (0.047) 0.120  (0.047)
Timepoint 15:00 (hours:minutes) 0.034  (0.047) 0.109  (0.047) 0.124  (0.047)
Timepoint 16:00 (hours:minutes) 0.050  (0.047) 0.111  (0.047) 0.116  (0.047)
Timepoint 18:00 (hours:minutes) 0.062  (0.046) 0.123  (0.046) 0.113  (0.046)
Timepoint 20:00 (hours:minutes) 0.036  (0.047) 0.125  (0.047) 0.088  (0.047)
Timepoint 22:00 (hours:minutes) 0.028  (0.048) 0.077  (0.048) 0.096  (0.048)
Timepoint 23:00 (hours:minutes) 0.018  (0.048) 0.094  (0.048) 0.062  (0.048)
Timepoint 23:50 (hours:minutes) -0.015  (0.049) 0.078  (0.049) 0.052  (0.049)
14.Secondary Outcome
Title Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L/min
Timepoint -0:10 (hours:minutes) 19.770  (7.357) 42.428  (7.378) 57.897  (7.359)
Timepoint 0:30 (hours:minutes) 12.994  (7.275) 46.272  (7.295) 58.436  (7.277)
Timepoint 1:00 (hours:minutes) 13.783  (7.027) 43.049  (7.043) 53.138  (7.028)
Timepoint 2:00 (hours:minutes) 11.366  (7.246) 48.328  (7.263) 55.826  (7.248)
Timepoint 3:00 (hours:minutes) 9.769  (7.457) 48.723  (7.474) 50.747  (7.458)
Timepoint 4:00 (hours:minutes) 7.499  (7.242) 42.599  (7.260) 50.077  (7.244)
Timepoint 11:50 (hours:minutes) -11.219  (7.747) 20.011  (7.765) 26.201  (7.749)
Timepoint 12:30 (hours:minutes) 4.345  (7.314) 27.436  (7.335) 33.887  (7.316)
Timepoint 13:00 (hours:minutes) 6.820  (7.479) 33.810  (7.499) 34.582  (7.481)
Timepoint 14:00 (hours:minutes) 13.879  (7.323) 44.786  (7.348) 43.371  (7.325)
Timepoint 15:00 (hours:minutes) 16.125  (6.992) 47.991  (7.012) 45.699  (6.994)
Timepoint 16:00 (hours:minutes) 19.616  (7.304) 47.697  (7.330) 46.441  (7.306)
Timepoint 18:00 (hours:minutes) 20.084  (7.303) 47.795  (7.326) 48.790  (7.306)
Timepoint 20:00 (hours:minutes) 13.348  (7.213) 42.240  (7.232) 40.888  (7.215)
Timepoint 22:00 (hours:minutes) 14.275  (7.317) 33.567  (7.339) 41.635  (7.319)
Timepoint 23:00 (hours:minutes) 13.590  (7.360) 36.712  (7.384) 38.384  (7.362)
Timepoint 23:50 (hours:minutes) 15.169  (7.670) 36.837  (7.697) 37.595  (7.673)
15.Secondary Outcome
Title FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time Frame 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L
0.003  (0.044) 0.104  (0.044) 0.087  (0.044)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.101
Confidence Interval 95%
0.055 to 0.147
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.084
Confidence Interval 95%
0.038 to 0.130
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.016
Confidence Interval 95%
-0.063 to 0.030
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R5 qd - Tio R2.5 bid
16.Secondary Outcome
Title PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min.
Time Frame 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 90 89 90
Mean (Standard Error)
Unit of Measure: L/min
8.589  (6.870) 38.831  (6.883) 42.899  (6.871)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 30.242
Confidence Interval 95%
22.167 to 38.317
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.091
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 34.310
Confidence Interval 95%
26.240 to 42.380
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.089
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.068
Confidence Interval 95%
-4.012 to 12.148
Parameter Dispersion
Type: Standard Error of the mean
Value: 4.094
Estimation Comments Tio R5 qd - Tio R2.5 bid
17.Secondary Outcome
Title PEF Variability Response (Last Week on Treatment)
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent (weekly means obtained during the last week of each period of randomised treatment will be compared).
Time Frame Baseline and during week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 88
Mean (Standard Error)
Unit of Measure: Percent
0.296  (0.711) 0.619  (0.718) 0.685  (0.721)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6747
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.323
Confidence Interval 95%
-1.195 to 1.841
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.769
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6159
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.389
Confidence Interval 95%
-1.138 to 1.916
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.774
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.065
Confidence Interval 95%
-1.468 to 1.599
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.777
Estimation Comments Tio R5 qd - Tio R2.5 bid
18.Secondary Outcome
Title Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values)
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
Time Frame Baseline and during week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 89
Mean (Standard Error)
Unit of Measure: Puffs
-0.841  (0.189) -0.917  (0.190) -1.016  (0.190)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5906
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.077
Confidence Interval 95%
-0.358 to 0.204
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.142
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2208
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.176
Confidence Interval 95%
-0.458 to 0.106
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.143
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.099
Confidence Interval 95%
-0.382 to 0.184
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.143
Estimation Comments Tio R5 qd - Tio R2.5 bid
19.Secondary Outcome
Title Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values)
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
Time Frame Baseline and during week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 89
Mean (Standard Error)
Unit of Measure: Puffs
-0.562  (0.106) -0.564  (0.106) -0.624  (0.106)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9797
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.002
Confidence Interval 95%
-0.163 to 0.159
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.082
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4518
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.062
Confidence Interval 95%
-0.223 to 0.100
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.082
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.060
Confidence Interval 95%
-0.222 to 0.102
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.082
Estimation Comments Tio R5 qd - Tio R2.5 bid
20.Secondary Outcome
Title Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values)
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
Time Frame Baseline and during week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 88
Mean (Standard Error)
Unit of Measure: Puffs
-0.358  (0.092) -0.419  (0.093) -0.432  (0.093)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4089
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.061
Confidence Interval 95%
-0.207 to 0.085
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.074
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3185
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.074
Confidence Interval 95%
-0.221 to 0.072
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.074
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.013
Confidence Interval 95%
-0.160 to 0.134
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.074
Estimation Comments Tio R5 qd - Tio R2.5 bid
21.Secondary Outcome
Title Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment.
Time Frame Baseline and during week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description:
Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed 91 89 88
Mean (Standard Error)
Unit of Measure: Night awakenings
-0.106  (0.028) -0.104  (0.029) -0.102  (0.029)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R2.5 Bid
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9626
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.001
Confidence Interval 95%
-0.059 to 0.062
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Tio R2.5 bid - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9102
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.003
Confidence Interval 95%
-0.058 to 0.065
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Tio R5 qd - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tio R2.5 Bid, Tio R5 qd
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.002
Confidence Interval 95%
-0.059 to 0.063
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Tio R5 qd - Tio R2.5 bid
Time Frame 4 weeks + 30 days if in last period
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Tio R2.5 Tio R5 qd
Hide Arm/Group Description Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS. Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS. Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
All-Cause Mortality
Placebo Tio R2.5 Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Tio R2.5 Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/92 (1.09%)   0/90 (0.00%)   2/90 (2.22%) 
Injury, poisoning and procedural complications       
Rib fracture  1  0/92 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Road traffic accident  1  0/92 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Vascular disorders       
Haemorrhage  1  0/92 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Hypertensive crisis  1  1/92 (1.09%)  0/90 (0.00%)  0/90 (0.00%) 
Venous thrombosis limb  1  0/92 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
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 R2.5 Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/92 (4.35%)   7/90 (7.78%)   5/90 (5.56%) 
Nervous system disorders       
Headache  1  4/92 (4.35%)  7/90 (7.78%)  5/90 (5.56%) 
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: NCT01152450     History of Changes
Other Study ID Numbers: 205.420
2009-018006-21 ( EudraCT Number: EudraCT )
First Submitted: June 28, 2010
First Posted: June 29, 2010
Results First Submitted: August 17, 2012
Results First Posted: October 30, 2012
Last Update Posted: May 16, 2014