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A Randomized, Double-Blind, 4-way Crossover Study to Evaluate the Efficacy of of 24 Hour Spirometry Profiles of Inhaled BI 1744 CL and Inhaled Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01040728
Recruitment Status : Completed
First Posted : December 30, 2009
Results First Posted : June 30, 2014
Last Update Posted : June 30, 2014
Sponsor:
Information provided by:
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: Olodaterol (BI1744) Low
Drug: Olodaterol (BI1744) High
Drug: Tiotropium 18 mcg
Drug: Placebo (for Olodaterol (BI1744)l)
Drug: Placebo (for Tiotropium)
Enrollment 122
Recruitment Details  
Pre-assignment Details This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments.
Arm/Group Title Placebo / Tio 18mcg / Olo 10mcg / Olo 5mcg Olo 5mcg / Olo 10mcg / Tio 18mcg / Placebo Olo 10mcg / Placebo / Olo 5mcg / Tio 18mcg Tio 18mcg / Olo 5mcg / Placebo / Olo 10mcg
Hide Arm/Group Description

Patients were administered placebo in the first period, Tiotropium 18 mcg qd in the second period, Olodaterol 10 mcg qd in the third period and Olodaterol 5 mcg qd in the fourth period.

Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.

Patients were administered Olodaterol 5 mcg qd in the first period, Olodaterol 10 mcg qd in the second period, Tiotropium 18 mcg qd in the third period and placebo in the fourth period.

Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.

Patients were administered Olodaterol 10 mcg qd in the first period, placebo in the second period, Olodaterol 5 mcg qd in the third period and Tiotropium 18 mcg qd in the fourth period.

Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.

Patients were administered Tiotropium 18 mcg qd in the first period, Olodaterol 5 mcg qd in the second period, placebo in the third period and Olodaterol 10 mcg qd in the fourth period.

Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.

Period Title: Overall Study
Started 31 30 31 30
Completed 27 19 30 24
Not Completed 4 11 1 6
Reason Not Completed
Adverse Event             4             8             0             4
Withdrawal by Subject             0             1             1             0
Protocol Violation             0             0             0             1
Lack of Efficacy             0             1             0             1
Other reasons not listed above             0             1             0             0
Arm/Group Title Study Total
Hide Arm/Group Description Total number of patients treated in the study. This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. 122 patients were assigned randomly to one of 4 treatment sequences in which they received each of 4 treatments, two doses (5 microgram (mcg) or 10 mcg) of Olodaterol (Olo) once daily (qd) delivered via the Respimat inhaler or Tiotropium (Tio) 18 mcg once daily (qd) delivered via the HandiHaler or equivalent placebo. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments.
Overall Number of Baseline Participants 122
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 122 participants
62.7  (7.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants
Female
47
  38.5%
Male
75
  61.5%
1.Primary Outcome
Title FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment
Hide Description Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the first morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS). FAS is defined as all patients with baseline (pre-dose) data and any evaluable post-dosing data for either of the co-primary endpoints. FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
-0.008  (0.019) 0.189  (0.019) 0.213  (0.019) 0.213  (0.019)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.197
Confidence Interval 95%
0.163 to 0.231
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.221
Confidence Interval 95%
0.186 to 0.255
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.221
Confidence Interval 95%
0.187 to 0.255
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Tio 18 mcg qd minus Placebo
2.Primary Outcome
Title FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment
Hide Description Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the first morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time Frame 1 h and 10 min prior to the am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
-0.059  (0.018) 0.094  (0.018) 0.111  (0.018) 0.105  (0.018)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.153
Confidence Interval 95%
0.117 to 0.188
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.170
Confidence Interval 95%
0.134 to 0.205
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.164
Confidence Interval 95%
0.128 to 0.199
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Tio 18 mcg qd minus Placebo
3.Secondary Outcome
Title Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment
Hide Description Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose at the first randomized treatment visit for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
-0.033  (0.019) 0.142  (0.018) 0.158  (0.018) 0.159  (0.018)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.175
Confidence Interval 95%
0.141 to 0.208
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.191
Confidence Interval 95%
0.157 to 0.225
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.192
Confidence Interval 95%
0.159 to 0.226
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Tio 18 mcg qd minus Placebo
4.Secondary Outcome
Title Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment
Hide Description Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the treatment at the first treatment visit for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.
Time Frame 1 hour (h) prior and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after first dose of treatment.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 107 113 113 111
Mean (Standard Error)
Unit of Measure: Liter
0.018  (0.018) 0.232  (0.017) 0.256  (0.017) 0.169  (0.018)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.214
Confidence Interval 95%
0.181 to 0.248
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.238
Confidence Interval 95%
0.205 to 0.272
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.152
Confidence Interval 95%
0.119 to 0.185
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.017
Estimation Comments Tio 18 mcg qd minus Placebo
5.Secondary Outcome
Title Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment
Hide Description Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.
Time Frame 1 hour (h) prior and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
0.011  (0.020) 0.225  (0.019) 0.255  (0.020) 0.246  (0.019)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.214
Confidence Interval 95%
0.178 to 0.251
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.245
Confidence Interval 95%
0.208 to 0.282
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.235
Confidence Interval 95%
0.199 to 0.271
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Tio 18 mcg qd minus Placebo
6.Secondary Outcome
Title Peak FEV1 (0-3h) Response
Hide Description Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of treatment for the first period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time Frame Study baseline and first day of dosing
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after first dose of treatment.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 107 113 113 111
Mean (Standard Error)
Unit of Measure: Liter
0.076  (0.019) 0.313  (0.019) 0.342  (0.019) 0.251  (0.019)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.237
Confidence Interval 95%
0.201 to 0.273
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.266
Confidence Interval 95%
0.230 to 0.302
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.175
Confidence Interval 95%
0.138 to 0.211
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Tio 18 mcg qd minus Placebo
7.Secondary Outcome
Title Peak FEV1 (0-3h) Response
Hide Description Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of treatment for the first period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time Frame Study baseline and 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
0.082  (0.020) 0.290  (0.020) 0.325  (0.020) 0.325  (0.020)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.208
Confidence Interval 95%
0.169 to 0.246
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.243
Confidence Interval 95%
0.205 to 0.282
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.020
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.244
Confidence Interval 95%
0.205 to 0.282
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Tio 18 mcg qd minus Placebo
8.Secondary Outcome
Title Trough FEV1 Response
Hide Description Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of treatment for the first period. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time Frame Study baseline and 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
0.003  (0.019) 0.137  (0.019) 0.146  (0.019) 0.161  (0.019)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.134
Confidence Interval 95%
0.097 to 0.171
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.143
Confidence Interval 95%
0.105 to 0.181
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.158
Confidence Interval 95%
0.120 to 0.195
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments Tio 18 mcg qd minus Placebo
9.Secondary Outcome
Title Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Hide Description Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment.
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
-0.006  (0.035) 0.324  (0.034) 0.321  (0.035) 0.364  (0.035)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.330
Confidence Interval 95%
0.276 to 0.384
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.326
Confidence Interval 95%
0.272 to 0.381
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.028
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.370
Confidence Interval 95%
0.316 to 0.424
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.027
Estimation Comments Tio 18 mcg qd minus Placebo
10.Secondary Outcome
Title FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Hide Description Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame 1 h and 10 min prior to the am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
-0.109  (0.036) 0.169  (0.035) 0.155  (0.036) 0.192  (0.035)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.278
Confidence Interval 95%
0.214 to 0.342
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.264
Confidence Interval 95%
0.200 to 0.329
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.302
Confidence Interval 95%
0.238 to 0.366
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Tio 18 mcg qd minus Placebo
11.Secondary Outcome
Title FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Hide Description Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
-0.057  (0.036) 0.247  (0.035) 0.226  (0.036) 0.278  (0.035)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.304
Confidence Interval 95%
0.244 to 0.363
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.283
Confidence Interval 95%
0.222 to 0.343
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.335
Confidence Interval 95%
0.275 to 0.395
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Tio 18 mcg qd minus Placebo
12.Secondary Outcome
Title FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
Hide Description Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after first dose of treatment.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 107 113 113 111
Mean (Standard Error)
Unit of Measure: Liter
0.053  (0.035) 0.423  (0.034) 0.419  (0.034) 0.316  (0.034)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.370
Confidence Interval 95%
0.309 to 0.430
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.366
Confidence Interval 95%
0.306 to 0.426
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.262
Confidence Interval 95%
0.202 to 0.322
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.030
Estimation Comments Tio 18 mcg qd minus Placebo
13.Secondary Outcome
Title FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
Hide Description Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to last dose of treatment after six weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
0.044  (0.035) 0.388  (0.034) 0.397  (0.035) 0.414  (0.034)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.344
Confidence Interval 95%
0.287 to 0.401
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.353
Confidence Interval 95%
0.296 to 0.411
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.370
Confidence Interval 95%
0.314 to 0.427
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.029
Estimation Comments Tio 18 mcg qd minus Placebo
14.Secondary Outcome
Title Peak FVC (0-3h) Response
Hide Description Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of treatment for the first period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last am dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time Frame Study baseline and 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 106 112
Mean (Standard Error)
Unit of Measure: Liter
0.191  (0.037) 0.526  (0.036) 0.537  (0.037) 0.569  (0.037)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.334
Confidence Interval 95%
0.272 to 0.396
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.346
Confidence Interval 95%
0.283 to 0.408
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.378
Confidence Interval 95%
0.316 to 0.440
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.031
Estimation Comments Tio 18 mcg qd minus Placebo
15.Secondary Outcome
Title Trough FVC Response
Hide Description Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose of treatment for the first period. Trough values were the mean of obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time Frame Study baseline and 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
FAS including all patients with evaluable data for this endpoint after six weeks.
Arm/Group Title Placebo Olo 5 mcg qd Olo 10 mcg qd Tio 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 105 115 107 112
Mean (Standard Error)
Unit of Measure: Liter
-0.001  (0.037) 0.243  (0.036) 0.215  (0.037) 0.255  (0.037)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 5 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.244
Confidence Interval 95%
0.179 to 0.309
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Olo 5 mcg qd minus Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Olo 10 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.216
Confidence Interval 95%
0.150 to 0.282
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Olo 10 mcg qd minus Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tio 18 mcg 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 Adjusted using a mixed model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.256
Confidence Interval 95%
0.191 to 0.321
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Tio 18 mcg qd minus Placebo
16.Secondary Outcome
Title Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Hide Description Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations).
Time Frame 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set.
Arm/Group Title Placebo Olo 5 mcg Olo 10 mcg Tiotropium (Tio) 18 mcg qd
Hide Arm/Group Description:
Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.
Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.
Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Overall Number of Participants Analyzed 109 115 113 113
Measure Type: Number
Unit of Measure: participants
Potassium increased 1 0 0 0
Atrial fibrillation 0 0 1 0
Palpitations 0 0 1 0
Time Frame 6 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Olo 5 mcg Olo 10 mcg Tiotropium (Tio) 18 mcg qd
Hide Arm/Group Description Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler. Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler. Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler. Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
All-Cause Mortality
Placebo Olo 5 mcg Olo 10 mcg Tiotropium (Tio) 18 mcg qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Olo 5 mcg Olo 10 mcg Tiotropium (Tio) 18 mcg qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/109 (4.59%)   3/115 (2.61%)   8/113 (7.08%)   2/113 (1.77%) 
Cardiac disorders         
Atrial fibrillation  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Cardiac ventricular disorder  1  0/109 (0.00%)  1/115 (0.87%)  0/113 (0.00%)  0/113 (0.00%) 
Eye disorders         
Retinal detachment  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Gastrointestinal disorders         
Upper gastrointestinal haemorrhage  1  1/109 (0.92%)  0/115 (0.00%)  0/113 (0.00%)  0/113 (0.00%) 
Infections and infestations         
Cellulitis staphylococcal  1  1/109 (0.92%)  0/115 (0.00%)  0/113 (0.00%)  0/113 (0.00%) 
Pneumonia  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Injury, poisoning and procedural complications         
Fracture displacement  1  1/109 (0.92%)  0/115 (0.00%)  0/113 (0.00%)  0/113 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Basal cell carcinoma  1  0/109 (0.00%)  0/115 (0.00%)  0/113 (0.00%)  1/113 (0.88%) 
Colon cancer  1  0/109 (0.00%)  1/115 (0.87%)  0/113 (0.00%)  0/113 (0.00%) 
Neuroendocrine carcinoma  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Renal cell carcinoma  1  0/109 (0.00%)  1/115 (0.87%)  0/113 (0.00%)  0/113 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  2/109 (1.83%)  0/115 (0.00%)  4/113 (3.54%)  1/113 (0.88%) 
Haemoptysis  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Pneumonitis  1  0/109 (0.00%)  0/115 (0.00%)  1/113 (0.88%)  0/113 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Olo 5 mcg Olo 10 mcg Tiotropium (Tio) 18 mcg qd
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/109 (7.34%)   14/115 (12.17%)   6/113 (5.31%)   4/113 (3.54%) 
Infections and infestations         
Nasopharyngitis  1  4/109 (3.67%)  8/115 (6.96%)  4/113 (3.54%)  4/113 (3.54%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  4/109 (3.67%)  6/115 (5.22%)  3/113 (2.65%)  1/113 (0.88%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
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, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01040728     History of Changes
Other Study ID Numbers: 1222.40
2009-014418-86 ( EudraCT Number: EudraCT )
First Submitted: December 29, 2009
First Posted: December 30, 2009
Results First Submitted: March 28, 2014
Results First Posted: June 30, 2014
Last Update Posted: June 30, 2014