Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Tiotropium+Olodaterol Fixed Dose Combination (FDC) in Chronic Obstructive Pulmonary Disease (OTEMTO 2)

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: NCT02006732
Recruitment Status : Completed
First Posted : December 10, 2013
Results First Posted : January 20, 2016
Last Update Posted : January 20, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: olodaterol
Drug: tiotropium
Drug: placebo
Enrollment 809
Recruitment Details 809 patients were randomised and treated.
Pre-assignment Details  
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description Once daily 2 puffs solution of placebo for inhalation with Respimat Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Period Title: Overall Study
Started 202 203 202 202
Completed 182 191 193 198
Not Completed 20 12 9 4
Reason Not Completed
Adverse Event             10             7             4             2
Lack of Efficacy             6             3             1             1
Protocol Violation             1             1             0             0
Lost to Follow-up             0             1             0             0
Withdrawal by Subject             3             0             4             1
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg Total
Hide Arm/Group Description Once daily 2 puffs solution of placebo for inhalation with Respimat Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. Total of all reporting groups
Overall Number of Baseline Participants 202 203 202 202 809
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 202 participants 203 participants 202 participants 202 participants 809 participants
64.0  (8.3) 64.7  (8.4) 64.4  (8.6) 65.2  (8.5) 64.6  (8.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 202 participants 203 participants 202 participants 202 participants 809 participants
Female
85
  42.1%
73
  36.0%
76
  37.6%
69
  34.2%
303
  37.5%
Male
117
  57.9%
130
  64.0%
126
  62.4%
133
  65.8%
506
  62.5%
1.Primary Outcome
Title FEV1 AUC0-3h Response
Hide Description Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
Time Frame baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from the Full Analysis Set (FAS): This patient set included all randomized and treated patients who had a baseline and at least one postbaseline measurement for any of the primary efficacy endpoints.
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 199 201 200 200
Mean (Standard Error)
Unit of Measure: L
-0.006  (0.014) 0.188  (0.013) 0.279  (0.014) 0.293  (0.013)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.299
Confidence Interval (2-Sided) 95%
0.261 to 0.336
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.105
Confidence Interval (2-Sided) 95%
0.069 to 0.141
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.284
Confidence Interval (2-Sided) 95%
0.246 to 0.323
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.020
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.091
Confidence Interval (2-Sided) 95%
0.053 to 0.128
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.194
Confidence Interval (2-Sided) 95%
0.156 to 0.232
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4499
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.014
Confidence Interval (2-Sided) 95%
-0.023 to 0.051
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
2.Primary Outcome
Title Trough FEV1 Response (Change From Baseline)
Hide Description Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
Time Frame baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 193 197 200 199
Mean (Standard Error)
Unit of Measure: L
-0.003  (0.014) 0.124  (0.013) 0.166  (0.013) 0.163  (0.013)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.166
Confidence Interval (2-Sided) 95%
0.129 to 0.203
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0395
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.039
Confidence Interval (2-Sided) 95%
0.002 to 0.076
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.169
Confidence Interval (2-Sided) 95%
0.132 to 0.207
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0269
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.042
Confidence Interval (2-Sided) 95%
0.005 to 0.079
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.127
Confidence Interval (2-Sided) 95%
0.090 to 0.165
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8669
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.003
Confidence Interval (2-Sided) 95%
-0.040 to 0.034
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.019
Estimation Comments [Not Specified]
3.Primary Outcome
Title St. George’s Respiratory Questionnaire (SGRQ) Total Score Based on Data From This Individual Study
Hide Description

The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life).

The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Time Frame 12 weeks treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 184 192 195 197
Mean (Standard Error)
Unit of Measure: units on a scale
42.575  (0.711) 39.729  (0.694) 38.909  (0.691) 38.011  (0.683)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.564
Confidence Interval (2-Sided) 95%
-6.499 to -2.629
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.986
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0780
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.717
Confidence Interval (2-Sided) 95%
-3.628 to 0.193
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.974
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.666
Confidence Interval (2-Sided) 95%
-5.611 to -1.721
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.991
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4028
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.820
Confidence Interval (2-Sided) 95%
-2.741 to 1.102
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.979
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.846
Confidence Interval (2-Sided) 95%
-4.796 to -0.897
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.993
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3555
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.898
Confidence Interval (2-Sided) 95%
-2.804 to 1.008
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.971
Estimation Comments [Not Specified]
4.Primary Outcome
Title St. George’s Respiratory Questionnaire (SGRQ) Total Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352
Hide Description

This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life).

The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Time Frame 12 weeks treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS after combining the data from this and the replicate study NCT01964352
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 370 384 394 393
Mean (Standard Error)
Unit of Measure: units on a scale
42.265  (0.511) 39.694  (0.498) 38.419  (0.494) 37.597  (0.492)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.668
Confidence Interval (2-Sided) 95%
-6.060 to -3.276
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.710
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.097
Confidence Interval (2-Sided) 95%
-3.471 to -0.723
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.701
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.846
Confidence Interval (2-Sided) 95%
-5.240 to -2.451
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.711
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0696
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.274
Confidence Interval (2-Sided) 95%
-2.651 to 0.102
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.702
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.571
Confidence Interval (2-Sided) 95%
-3.971 to -1.171
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.714
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2387
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.822
Confidence Interval (2-Sided) 95%
-2.191 to 0.546
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.698
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Trough Forced Vital Capacity (FVC) Response (Change From Baseline)
Hide Description Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
Time Frame baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 193 197 200 199
Mean (Standard Error)
Unit of Measure: L
-0.021  (0.024) 0.170  (0.023) 0.284  (0.023) 0.231  (0.023)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.252
Confidence Interval (2-Sided) 95%
0.187 to 0.317
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0614
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.061
Confidence Interval (2-Sided) 95%
-0.003 to 0.125
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.305
Confidence Interval (2-Sided) 95%
0.240 to 0.370
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.114
Confidence Interval (2-Sided) 95%
0.049 to 0.178
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.191
Confidence Interval (2-Sided) 95%
0.126 to 0.256
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1089
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.053
Confidence Interval (2-Sided) 95%
-0.117 to 0.012
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
6.Secondary Outcome
Title TDI Focal Score Based on Data From This Individual Study
Hide Description

Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9).

The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 183 192 195 197
Mean (Standard Error)
Unit of Measure: Units on a scale
0.337  (0.195) 0.950  (0.191) 1.599  (0.189) 1.531  (0.187)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.195
Confidence Interval (2-Sided) 95%
0.665 to 1.725
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.270
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0296
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.582
Confidence Interval (2-Sided) 95%
0.058 to 1.106
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.267
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.263
Confidence Interval (2-Sided) 95%
0.730 to 1.796
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.272
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0159
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.650
Confidence Interval (2-Sided) 95%
0.122 to 1.178
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.269
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0248
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.613
Confidence Interval (2-Sided) 95%
0.078 to 1.148
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.273
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7984
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.068
Confidence Interval (2-Sided) 95%
-0.590 to 0.454
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.266
Estimation Comments [Not Specified]
7.Secondary Outcome
Title TDI Focal Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352
Hide Description

This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9).

The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.

Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS after combining the data from this and the replicate study NCT01964352
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 370 385 394 393
Mean (Standard Error)
Unit of Measure: Units on a scale
0.111  (0.139) 1.140  (0.136) 1.722  (0.134) 1.734  (0.134)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.623
Confidence Interval (2-Sided) 95%
1.245 to 2.000
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.193
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.594
Confidence Interval (2-Sided) 95%
0.220 to 0.967
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.190
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.611
Confidence Interval (2-Sided) 95%
1.232 to 1.989
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.193
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.582
Confidence Interval (2-Sided) 95%
0.207 to 0.956
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.191
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.029
Confidence Interval (2-Sided) 95%
0.649 to 1.410
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.194
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9494
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.012
Confidence Interval (2-Sided) 95%
-0.359 to 0.383
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.189
Estimation Comments [Not Specified]
8.Secondary Outcome
Title FVC AUC0-3h Response (Change From Baseline)
Hide Description The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
Time Frame baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Patients from FAS
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
Hide Arm/Group Description:
Once daily 2 puffs solution of placebo for inhalation with Respimat
Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
Overall Number of Participants Analyzed 199 201 200 200
Mean (Standard Error)
Unit of Measure: L
-0.018  (0.025) 0.266  (0.023) 0.436  (0.024) 0.414  (0.023)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.432
Confidence Interval (2-Sided) 95%
0.366 to 0.498
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.148
Confidence Interval (2-Sided) 95%
0.084 to 0.212
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.455
Confidence Interval (2-Sided) 95%
0.387 to 0.522
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 μg, Tiotropium 2.5 μg+ Olodaterol 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.171
Confidence Interval (2-Sided) 95%
0.105 to 0.236
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium 5 μg
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 Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.284
Confidence Interval (2-Sided) 95%
0.217 to 0.350
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 2.5 μg+ Olodaterol 5 μg, Tiotropium 5 μg + Olodaterol 5 μg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4974
Comments [Not Specified]
Method Mixed Effects Model for Repeated Measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.022
Confidence Interval (2-Sided) 95%
-0.087 to 0.042
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments [Not Specified]
Time Frame up to 112 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Tiotropium 5 μg Tiotropium 2.5 μg +Olodaterol 5 μg Tiotropium 5 μg +Olodaterol 5 μg
Hide Arm/Group Description Once daily 2 puffs solution of placebo for inhalation with Respimat Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.
All-Cause Mortality
Placebo Tiotropium 5 μg Tiotropium 2.5 μg +Olodaterol 5 μg Tiotropium 5 μg +Olodaterol 5 μg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Tiotropium 5 μg Tiotropium 2.5 μg +Olodaterol 5 μg Tiotropium 5 μg +Olodaterol 5 μg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/202 (1.98%)   12/203 (5.91%)   4/202 (1.98%)   6/202 (2.97%) 
Cardiac disorders         
Atrial fibrillation  1  0/202 (0.00%)  0/203 (0.00%)  0/202 (0.00%)  1/202 (0.50%) 
Myocardial infarction  1  0/202 (0.00%)  2/203 (0.99%)  0/202 (0.00%)  1/202 (0.50%) 
Acute coronary syndrome  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Acute myocardial infarction  1  0/202 (0.00%)  0/203 (0.00%)  0/202 (0.00%)  1/202 (0.50%) 
Angina pectoris  1  1/202 (0.50%)  0/203 (0.00%)  0/202 (0.00%)  0/202 (0.00%) 
Supraventricular tachycardia  1  1/202 (0.50%)  0/203 (0.00%)  0/202 (0.00%)  0/202 (0.00%) 
Eye disorders         
Blindness  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Gastrointestinal disorders         
Large intestine polyp  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Nausea  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Umbilical hernia  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Infections and infestations         
Cellulitis  1  0/202 (0.00%)  0/203 (0.00%)  1/202 (0.50%)  0/202 (0.00%) 
Diverticulitis  1  1/202 (0.50%)  0/203 (0.00%)  0/202 (0.00%)  0/202 (0.00%) 
Injury, poisoning and procedural complications         
Ankle fracture  1  0/202 (0.00%)  0/203 (0.00%)  1/202 (0.50%)  0/202 (0.00%) 
Musculoskeletal and connective tissue disorders         
Musculoskeletal chest pain  1  0/202 (0.00%)  2/203 (0.99%)  1/202 (0.50%)  0/202 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Basal cell carcinoma  1  0/202 (0.00%)  0/203 (0.00%)  0/202 (0.00%)  1/202 (0.50%) 
Prostate cancer  1  1/202 (0.50%)  0/203 (0.00%)  0/202 (0.00%)  0/202 (0.00%) 
Squamous cell carcinoma  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Nervous system disorders         
Carotid artery stenosis  1  0/202 (0.00%)  0/203 (0.00%)  0/202 (0.00%)  1/202 (0.50%) 
Psychiatric disorders         
Alcoholism  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  1/202 (0.50%)  1/203 (0.49%)  0/202 (0.00%)  1/202 (0.50%) 
Acute respiratory failure  1  0/202 (0.00%)  0/203 (0.00%)  0/202 (0.00%)  1/202 (0.50%) 
Pulmonary embolism  1  0/202 (0.00%)  0/203 (0.00%)  1/202 (0.50%)  0/202 (0.00%) 
Skin and subcutaneous tissue disorders         
Rash  1  0/202 (0.00%)  0/203 (0.00%)  1/202 (0.50%)  0/202 (0.00%) 
Vascular disorders         
Hypertension  1  0/202 (0.00%)  1/203 (0.49%)  0/202 (0.00%)  0/202 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Tiotropium 5 μg Tiotropium 2.5 μg +Olodaterol 5 μg Tiotropium 5 μg +Olodaterol 5 μg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   34/202 (16.83%)   15/203 (7.39%)   25/202 (12.38%)   14/202 (6.93%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  14/202 (6.93%)  7/203 (3.45%)  17/202 (8.42%)  9/202 (4.46%) 
Cough  1  12/202 (5.94%)  5/203 (2.46%)  5/202 (2.48%)  3/202 (1.49%) 
Dyspnoea  1  14/202 (6.93%)  4/203 (1.97%)  4/202 (1.98%)  2/202 (0.99%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
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.
Other - Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02006732     History of Changes
Other Study ID Numbers: 1237.26
2013-002264-24 ( EudraCT Number: EudraCT )
First Submitted: October 14, 2013
First Posted: December 10, 2013
Results First Submitted: October 23, 2015
Results First Posted: January 20, 2016
Last Update Posted: January 20, 2016