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Tiotropium+Olodaterol Fixed Dose Combination (FDC) Versus Tiotropium and Olodaterol in Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT01431274
Recruitment Status : Completed
First Posted : September 9, 2011
Results First Posted : July 16, 2015
Last Update Posted : July 16, 2015
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: tiotropium + olodaterol
Drug: tiotropium
Drug: olodaterol
Device: Respimat
Enrollment 2624
Recruitment Details  
Pre-assignment Details This trial was one of 2 confirmatory Phase III 52-week, multi-centre, multi-national, randomised,double-blind, parallel group studies to evaluate the long-term efficacy and safety of once daily treatment with orally inhaled Tio+Olo FDC (2.5/5μg; 5/5μg) compared with the individual components (2.5μg; 5μg Tiotropium, 5μg Olodaterol) in COPD patients
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Period Title: Overall Study
Started 528 525 527 522 522
Completed 431 448 455 462 466
Not Completed 97 77 72 60 56
Reason Not Completed
Adverse Event             51             37             43             30             37
Consent withdrawn not due to AE             29             20             17             20             11
Non compliant with protocol             5             8             4             4             4
Lost to Follow-up             6             7             1             4             0
Other reason not stated above             6             5             7             2             4
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg) Total
Hide Arm/Group Description Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning. Total of all reporting groups
Overall Number of Baseline Participants 528 525 527 522 522 2624
Hide Baseline Analysis Population Description
Treated set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 528 participants 525 participants 527 participants 522 participants 522 participants 2624 participants
63.7  (8.0) 64.2  (8.6) 64.2  (8.5) 64.1  (8.0) 64.8  (8.2) 64.2  (8.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 528 participants 525 participants 527 participants 522 participants 522 participants 2624 participants
Female
142
  26.9%
133
  25.3%
144
  27.3%
133
  25.5%
138
  26.4%
690
  26.3%
Male
386
  73.1%
392
  74.7%
383
  72.7%
389
  74.5%
384
  73.6%
1934
  73.7%
1.Primary Outcome
Title Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.
Hide Description

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an 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 random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.

Time Frame 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full analysis set (FAS) included all patients who were randomised, who were dispensed study medication, were documented to have taken any dose of study medication and who had a non-missing baseline and at least one non-missing post-baseline measurement before or at Week 24 for any of the primary and key secondary efficacy endpoints.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 525 524 526 521 522
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.133  (0.008) 0.148  (0.008) 0.139  (0.008) 0.241  (0.008) 0.256  (0.008)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.123
Confidence Interval (2-Sided) 95%
0.100 to 0.146
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.117
Confidence Interval 95%
0.094 to 0.140
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.109
Confidence Interval (2-Sided) 95%
0.086 to 0.132
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.093
Confidence Interval (2-Sided) 95%
0.070 to 0.116
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.102
Confidence Interval (2-Sided) 95%
0.080 to 0.125
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2169
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.014
Confidence Interval (2-Sided) 95%
-0.008 to 0.037
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.108
Confidence Interval (2-Sided) 95%
0.085 to 0.130
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5849
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.006
Confidence Interval (2-Sided) 95%
-0.017 to 0.029
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1863
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.016
Confidence Interval (2-Sided) 95%
-0.007 to 0.039
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4352
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.009
Confidence Interval (2-Sided) 95%
-0.032 to 0.014
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

2.Primary Outcome
Title Trough FEV1 Response on Day 170.
Hide Description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

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

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 519 519 520 518 521
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.054  (0.009) 0.083  (0.008) 0.065  (0.008) 0.111  (0.008) 0.136  (0.008)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.082
Confidence Interval (2-Sided) 95%
0.059 to 0.106
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.071
Confidence Interval (2-Sided) 95%
0.047 to 0.094
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.058
Confidence Interval (2-Sided) 95%
0.034 to 0.081
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0174
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.029
Confidence Interval (2-Sided) 95%
0.005 to 0.052
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.046
Confidence Interval (2-Sided) 95%
0.023 to 0.070
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0407
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.024
Confidence Interval (2-Sided) 95%
0.001 to 0.048
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.053
Confidence Interval (2-Sided) 95%
0.030 to 0.077
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3326
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.012
Confidence Interval (2-Sided) 95%
-0.012 to 0.035
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0151
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.029
Confidence Interval (2-Sided) 95%
0.006 to 0.053
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1421
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.018
Confidence Interval (2-Sided) 95%
-0.041 to 0.006
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

3.Primary Outcome
Title Saint George’s Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Hide Description The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Time Frame Day 169
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 954 960 954 990 979
Least Squares Mean (Standard Error)
Unit of Measure: points on a scale
38.366  (0.396) 37.792  (0.390) 37.907  (0.393) 37.335  (0.385) 36.674  (0.386)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -1.693
Confidence Interval (2-Sided) 95%
-2.778 to -0.608
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.553
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0252
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -1.233
Confidence Interval (2-Sided) 95%
-2.313 to -0.153
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.551
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0620
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -1.031
Confidence Interval (2-Sided) 95%
-2.113 to 0.052
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.552
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4051
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.456
Confidence Interval (2-Sided) 95%
-1.531 to 0.618
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.548
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2988
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.571
Confidence Interval (2-Sided) 95%
-1.649 to 0.507
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.550
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2249
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.662
Confidence Interval (2-Sided) 95%
-1.731 to 0.407
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.545
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0418
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -1.118
Confidence Interval (2-Sided) 95%
-2.195 to -0.042
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.549
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4097
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.460
Confidence Interval (2-Sided) 95%
-1.552 to 0.633
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.557
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg)

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3013
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.575
Confidence Interval (2-Sided) 95%
-1.664 to 0.515
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.556
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8355
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.115
Confidence Interval (2-Sided) 95%
-0.970 to 1.200
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.554
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

4.Secondary Outcome
Title Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Hide Description

Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) is the key secondary endpoint.

The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Time Frame Day 169
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 984 982 978 992 992
Least Squares Mean (Standard Error)
Unit of Measure: points on a scale
1.564  (0.096) 1.690  (0.095) 1.627  (0.096) 1.980  (0.095) 1.983  (0.095)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.420
Confidence Interval (2-Sided) 95%
0.155 to 0.684
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0082
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.356
Confidence Interval (2-Sided) 95%
0.092 to 0.619
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.416
Confidence Interval (2-Sided) 95%
0.152 to 0.681
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0307
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.290
Confidence Interval (2-Sided) 95%
0.027 to 0.554
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.134
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0088
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.352
Confidence Interval (2-Sided) 95%
0.089 to 0.616
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9801
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.003
Confidence Interval (2-Sided) 95%
-0.259 to 0.266
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.134
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0289
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.294
Confidence Interval (2-Sided) 95%
0.030 to 0.557
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.134
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6382
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.064
Confidence Interval (2-Sided) 95%
-0.202 to 0.330
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.136
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3525
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.126
Confidence Interval (2-Sided) 95%
-0.140 to 0.391
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6457
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.062
Confidence Interval (2-Sided) 95%
-0.327 to 0.203
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.135
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

5.Secondary Outcome
Title FEV1 AUC(0-3h) Response on Day 1
Hide Description

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an 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 random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 525 524 526 521 522
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.205  (0.009) 0.148  (0.009) 0.157  (0.009) 0.226  (0.009) 0.237  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0067
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.033
Confidence Interval (2-Sided) 95%
0.009 to 0.056
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.081
Confidence Interval (2-Sided) 95%
0.057 to 0.104
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0746
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.022
Confidence Interval (2-Sided) 95%
-0.002 to 0.045
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.078
Confidence Interval (2-Sided) 95%
0.054 to 0.101
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.070
Confidence Interval (2-Sided) 95%
0.046 to 0.093
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3549
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.011
Confidence Interval (2-Sided) 95%
-0.013 to 0.035
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.089
Confidence Interval (2-Sided) 95%
0.065 to 0.113
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), 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 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.048
Confidence Interval (2-Sided) 95%
-0.072 to -0.025
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.056
Confidence Interval (2-Sided) 95%
-0.080 to -0.033
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5018
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.008
Confidence Interval (2-Sided) 95%
-0.016 to 0.032
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

6.Secondary Outcome
Title FEV1 AUC(0-3h) Response on Day 85
Hide Description

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an 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 random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 525 524 526 521 522
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.161  (0.009) 0.176  (0.009) 0.162  (0.009) 0.271  (0.009) 0.289  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.128
Confidence Interval (2-Sided) 95%
0.104 to 0.152
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.126
Confidence Interval (2-Sided) 95%
0.102 to 0.150
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.111
Confidence Interval (2-Sided) 95%
0.087 to 0.135
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.096
Confidence Interval (2-Sided) 95%
0.072 to 0.120
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.109
Confidence Interval (2-Sided) 95%
0.085 to 0.133
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1569
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.017
Confidence Interval (2-Sided) 95%
-0.007 to 0.041
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.113
Confidence Interval (2-Sided) 95%
0.089 to 0.137
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8834
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.002
Confidence Interval (2-Sided) 95%
-0.022 to 0.026
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2129
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.015
Confidence Interval (2-Sided) 95%
-0.009 to 0.039
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2702
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.013
Confidence Interval (2-Sided) 95%
-0.037 to 0.010
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

7.Secondary Outcome
Title FEV1 AUC(0-3h) Response on Day 365
Hide Description

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an 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 random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (on day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 525 524 526 521 522
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.096  (0.009) 0.116  (0.009) 0.122  (0.009) 0.214  (0.009) 0.237  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.141
Confidence Interval (2-Sided) 95%
0.117 to 0.166
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.115
Confidence Interval (2-Sided) 95%
0.090 to 0.139
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.119
Confidence Interval (2-Sided) 95%
0.094 to 0.143
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.099
Confidence Interval (2-Sided) 95%
0.074 to 0.123
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.092
Confidence Interval (2-Sided) 95%
0.067 to 0.117
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0717
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.023
Confidence Interval (2-Sided) 95%
-0.002 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.121
Confidence Interval (2-Sided) 95%
0.097 to 0.146
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0344
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.027
Confidence Interval (2-Sided) 95%
0.002 to 0.051
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1126
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.020
Confidence Interval (2-Sided) 95%
-0.005 to 0.045
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6009
Comments 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.
Method Mixed Models Analysis
Comments Kenward−Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.007
Confidence Interval (2-Sided) 95%
-0.018 to 0.031
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

8.Secondary Outcome
Title Trough FEV1 Response on Day 15.
Hide Description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed

1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (day 15). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 519 519 520 518 521
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.085  (0.009) 0.101  (0.009) 0.094  (0.009) 0.132  (0.009) 0.157  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.072
Confidence Interval (2-Sided) 95%
0.049 to 0.096
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.063
Confidence Interval (2-Sided) 95%
0.039 to 0.087
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.047
Confidence Interval (2-Sided) 95%
0.023 to 0.070
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0122
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.030
Confidence Interval (2-Sided) 95%
0.007 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0021
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.037
Confidence Interval (2-Sided) 95%
0.014 to 0.061
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0347
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.026
Confidence Interval (2-Sided) 95%
0.002 to 0.049
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.056
Confidence Interval (2-Sided) 95%
0.032 to 0.080
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4407
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.009
Confidence Interval (2-Sided) 95%
-0.014 to 0.033
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1777
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.016
Confidence Interval (2-Sided) 95%
-0.007 to 0.040
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5641
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.007
Confidence Interval (2-Sided) 95%
-0.031 to 0.017
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

9.Secondary Outcome
Title Trough FEV1 Response on Day 43
Hide Description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed

1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (day 43). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 519 519 520 518 521
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.083  (0.009) 0.097  (0.009) 0.088  (0.009) 0.120  (0.009) 0.163  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.080
Confidence Interval (2-Sided) 95%
0.057 to 0.104
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.075
Confidence Interval (2-Sided) 95%
0.051 to 0.099
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0018
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.038
Confidence Interval (2-Sided) 95%
0.014 to 0.062
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0517
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.024
Confidence Interval (2-Sided) 95%
-0.000 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0072
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.033
Confidence Interval (2-Sided) 95%
0.009 to 0.056
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.042
Confidence Interval (2-Sided) 95%
0.019 to 0.066
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.066
Confidence Interval (2-Sided) 95%
0.042 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6619
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.005
Confidence Interval (2-Sided) 95%
-0.018 to 0.029
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2401
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.014
Confidence Interval (2-Sided) 95%
-0.010 to 0.038
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4601
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.009
Confidence Interval (2-Sided) 95%
-0.033 to 0.015
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

10.Secondary Outcome
Title Trough FEV1 Response on Day 85
Hide Description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed

1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 519 519 520 518 521
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.057  (0.009) 0.077  (0.009) 0.070  (0.009) 0.128  (0.009) 0.146  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.064 to 0.112
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.076
Confidence Interval (2-Sided) 95%
0.052 to 0.100
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.070
Confidence Interval (2-Sided) 95%
0.046 to 0.094
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.051
Confidence Interval (2-Sided) 95%
0.027 to 0.075
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.058
Confidence Interval (2-Sided) 95%
0.034 to 0.082
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1405
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.018
Confidence Interval (2-Sided) 95%
-0.006 to 0.042
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.069
Confidence Interval (2-Sided) 95%
0.045 to 0.093
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3118
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.012
Confidence Interval (2-Sided) 95%
-0.012 to 0.036
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tiotropium (2.5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1171
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.019
Confidence Interval (2-Sided) 95%
-0.005 to 0.043
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (2.5 µg) versus Olodaterol (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tiotropium (5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5759
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value -0.007
Confidence Interval (2-Sided) 95%
-0.031 to 0.017
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tiotropium (5 µg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

11.Secondary Outcome
Title Trough FEV1 Response on Day 169
Hide Description

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed

1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Time Frame 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (day 169). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
Arm/Group Title Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
Hide Arm/Group Description:
Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 519 519 520 518 521
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.033  (0.009) 0.047  (0.009) 0.050  (0.009) 0.094  (0.009) 0.112  (0.009)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.079
Confidence Interval (2-Sided) 95%
0.055 to 0.103
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.062
Confidence Interval (2-Sided) 95%
0.038 to 0.086
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.061
Confidence Interval (2-Sided) 95%
0.037 to 0.085
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.047
Confidence Interval (2-Sided) 95%
0.022 to 0.071
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments 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.
Method Mixed Models Analysis
Comments Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation Estimation Parameter Adjusted mean difference
Estimated Value 0.044
Confidence Interval (2-Sided) 95%
0.019 to 0.068
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments

Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg).

Spatial power covariance structure for within−patient errors.

Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1360
Comments