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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: NCT01431287
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 2539
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 510 [1] 507 507 508 507
Completed 412 409 410 445 430
Not Completed 98 98 97 63 77
Reason Not Completed
not treated             0             0             1             0             0
Adverse Event             59             57             53             33             41
Non compliant with protocol             6             6             5             6             5
Lost to Follow-up             0             3             2             3             1
Consent withdrawn not due to AE             29             30             34             19             29
not stated above             4             2             2             2             1
[1]
started are actually the randomized
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 in the morning. Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning. Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning. Oral inhalation of 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 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 in the morning. Total of all reporting groups
Overall Number of Baseline Participants 510 507 506 508 507 2538
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 510 participants 507 participants 506 participants 508 participants 507 participants 2538 participants
64.7  (8.3) 63.9  (8.7) 63.5  (8.7) 64.1  (7.6) 62.7  (8.4) 63.8  (8.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 510 participants 507 participants 506 participants 508 participants 507 participants 2538 participants
Female
132
  25.9%
146
  28.8%
134
  26.5%
140
  27.6%
158
  31.2%
710
  28.0%
Male
378
  74.1%
361
  71.2%
372
  73.5%
368
  72.4%
349
  68.8%
1828
  72.0%
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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 507 504 500 506 502
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.136  (0.009) 0.125  (0.009) 0.165  (0.009) 0.256  (0.009) 0.268  (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 0.132
Confidence Interval (2-Sided) 95%
0.108 to 0.157
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.103
Confidence Interval (2-Sided) 95%
0.078 to 0.127
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.121
Confidence Interval (2-Sided) 95%
0.096 to 0.145
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.131
Confidence Interval (2-Sided) 95%
0.106 to 0.155
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.091
Confidence Interval (2-Sided) 95%
0.066 to 0.115
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.3394
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%
-0.013 to 0.036
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.143
Confidence Interval (2-Sided) 95%
0.118 to 0.167
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0173
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%
0.005 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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 0.4210
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 -0.010
Confidence Interval (2-Sided) 95%
-0.035 to 0.014
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0014
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 0.040
Confidence Interval (2-Sided) 95%
0.015 to 0.064
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.012
Estimation Comments 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 503 499 498 500 497
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.057  (0.009) 0.062  (0.009) 0.096  (0.009) 0.125  (0.009) 0.145  (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%
0.063 to 0.113
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.050
Confidence Interval (2-Sided) 95%
0.024 to 0.075
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.067
Confidence Interval (2-Sided) 95%
0.042 to 0.092
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.062
Confidence Interval (2-Sided) 95%
0.037 to 0.087
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0231
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%
0.004 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.1073
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 0.021
Confidence Interval (2-Sided) 95%
-0.004 to 0.046
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.083
Confidence Interval (2-Sided) 95%
0.058 to 0.108
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0029
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%
0.013 to 0.063
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.6939
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%
-0.020 to 0.030
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0097
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%
0.008 to 0.058
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 1237.6 (NCT01431287) and 1237.5 (NCT01431274).
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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 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 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 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 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 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 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 0.2249
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 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 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 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 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 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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Hide Description

Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 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 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 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 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 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 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 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 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 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 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 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 507 504 500 506 502
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.196  (0.009) 0.135  (0.009) 0.164  (0.009) 0.228  (0.009) 0.229  (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 0.0095
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%
0.008 to 0.058
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.065
Confidence Interval (2-Sided) 95%
0.040 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0112
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%
0.007 to 0.058
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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%
0.068 to 0.119
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.064
Confidence Interval (2-Sided) 95%
0.039 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.9514
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 0.001
Confidence Interval (2-Sided) 95%
-0.024 to 0.026
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.094
Confidence Interval (2-Sided) 95%
0.069 to 0.119
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0131
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 -0.032
Confidence Interval (2-Sided) 95%
-0.057 to -0.007
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 -0.061
Confidence Interval (2-Sided) 95%
-0.086 to -0.036
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0243
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%
0.004 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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
Hide Outcome Measure Data
Hide Analysis Population Description
FAS (on 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 507 504 500 506 502
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.153  (0.009) 0.165  (0.009) 0.187  (0.009) 0.272  (0.009) 0.297  (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 0.145
Confidence Interval (2-Sided) 95%
0.119 to 0.170
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.111
Confidence Interval (2-Sided) 95%
0.085 to 0.136
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.144
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.106
Confidence Interval (2-Sided) 95%
0.081 to 0.132
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.085
Confidence Interval (2-Sided) 95%
0.059 to 0.110
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0470
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%
0.000 to 0.051
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.132
Confidence Interval (2-Sided) 95%
0.107 to 0.158
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0083
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 0.034
Confidence Interval (2-Sided) 95%
0.009 to 0.060
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.3329
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%
-0.013 to 0.038
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0958
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%
-0.004 to 0.047
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 507 504 500 506 502
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.105  (0.010) 0.105  (0.010) 0.124  (0.010) 0.223  (0.009) 0.237  (0.010)
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 0.132
Confidence Interval (2-Sided) 95%
0.105 to 0.158
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments 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 0.112
Confidence Interval (2-Sided) 95%
0.086 to 0.139
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments 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 0.118
Confidence Interval (2-Sided) 95%
0.092 to 0.144
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.118
Confidence Interval (2-Sided) 95%
0.092 to 0.144
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.098
Confidence Interval (2-Sided) 95%
0.072 to 0.125
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.3008
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%
-0.012 to 0.040
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.132
Confidence Interval (2-Sided) 95%
0.105 to 0.158
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments 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 0.1484
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%
-0.007 to 0.046
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments 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 0.9981
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 0.000
Confidence Interval (2-Sided) 95%
-0.026 to 0.027
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.014
Estimation Comments 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 0.1480
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%
-0.007 to 0.046
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 503 499 498 500 497
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.083  (0.009) 0.085  (0.009) 0.112  (0.009) 0.147  (0.009) 0.148  (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 0.065
Confidence Interval (2-Sided) 95%
0.040 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0050
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 0.036
Confidence Interval (2-Sided) 95%
0.011 to 0.061
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.064
Confidence Interval (2-Sided) 95%
0.039 to 0.089
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.063
Confidence Interval (2-Sided) 95%
0.037 to 0.088
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0057
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 0.036
Confidence Interval (2-Sided) 95%
0.010 to 0.061
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.9633
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 0.001
Confidence Interval (2-Sided) 95%
-0.025 to 0.026
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.063
Confidence Interval (2-Sided) 95%
0.038 to 0.088
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0250
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%
0.004 to 0.054
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.8949
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%
-0.023 to 0.027
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0351
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 0.052
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 503 499 498 500 497
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.070  (0.009) 0.085  (0.009) 0.103  (0.009) 0.146  (0.009) 0.150  (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%
0.055 to 0.105
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0002
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 0.073
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.076
Confidence Interval (2-Sided) 95%
0.051 to 0.101
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.061
Confidence Interval (2-Sided) 95%
0.036 to 0.086
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0007
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%
0.018 to 0.069
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.7755
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 0.004
Confidence Interval (2-Sided) 95%
-0.022 to 0.029
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.065
Confidence Interval (2-Sided) 95%
0.039 to 0.090
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0118
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 0.032
Confidence Interval (2-Sided) 95%
0.007 to 0.058
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.2416
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%
-0.010 to 0.040
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.1792
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%
-0.008 to 0.043
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 1hr and 10 min pre-dose on day 85
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 503 499 498 500 497
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.047  (0.009) 0.081  (0.009) 0.088  (0.009) 0.129  (0.009) 0.147  (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 0.100
Confidence Interval (2-Sided) 95%
0.074 to 0.125
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.059
Confidence Interval (2-Sided) 95%
0.033 to 0.084
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.082
Confidence Interval (2-Sided) 95%
0.057 to 0.107
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.048
Confidence Interval (2-Sided) 95%
0.023 to 0.073
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0014
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 0.041
Confidence Interval (2-Sided) 95%
0.016 to 0.067
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.1747
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%
-0.008 to 0.043
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.065
Confidence Interval (2-Sided) 95%
0.040 to 0.091
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0016
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 0.041
Confidence Interval (2-Sided) 95%
0.016 to 0.066
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0081
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 0.034
Confidence Interval (2-Sided) 95%
0.009 to 0.060
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.6110
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%
-0.019 to 0.032
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 1hr and 10 min pre-dose on day 169
Hide 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 in the morning.
Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.
Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.
Oral inhalation of 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 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 in the morning.
Overall Number of Participants Analyzed 503 499 498 500 497
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.034  (0.009) 0.041  (0.009) 0.068  (0.009) 0.111  (0.009) 0.119  (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 0.085
Confidence Interval (2-Sided) 95%
0.059 to 0.111
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.050
Confidence Interval (2-Sided) 95%
0.025 to 0.076
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.077
Confidence Interval (2-Sided) 95%
0.051 to 0.102
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.069
Confidence Interval (2-Sided) 95%
0.044 to 0.095
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0013
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%
0.016 to 0.068
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.5274
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%
-0.017 to 0.034
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.078
Confidence Interval (2-Sided) 95%
0.052 to 0.103
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.013
Estimation Comments 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 0.0083
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