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

• ClinicalTrials.gov Identifier: NCT01431274
• Recruitment Status: Completed
• First Posted: September 9, 2011
• Results First Posted: July 16, 2015
• Last Update Posted: July 16, 2015
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Pulmonary Disease, Chronic Obstructive
• Interventions: Drug: tiotropium + olodaterol; Drug: tiotropium; Drug: olodaterol; Device: Respimat
• Enrollment: 2624

Participant Flow

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)
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Period Title: Overall Study
Started	528	525	527	522	522
Completed	431	448	455	462	466
Not Completed	97	77	72	60	56
Reason Not Completed
Adverse Event	51	37	43	30	37
Consent withdrawn not due to AE	29	20	17	20	11
Non compliant with protocol	5	8	4	4	4
Lost to Follow-up	6	7	1	4	0
Other reason not stated above	6	5	7	2	4

Baseline Characteristics

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
Arm/Group Description		Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Total of all reporting groups
Overall Number of Baseline Participants		528	525	527	522	522	2624
Baseline Analysis Population Description		Treated set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	528 participants	525 participants	527 participants	522 participants	522 participants	2624 participants
		63.7 (8.0)	64.2 (8.6)	64.2 (8.5)	64.1 (8.0)	64.8 (8.2)	64.2 (8.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	528 participants	525 participants	527 participants	522 participants	522 participants	2624 participants
	Female	142 26.9%	133 25.3%	144 27.3%	133 25.5%	138 26.4%	690 26.3%
	Male	386 73.1%	392 74.7%	383 72.7%	389 74.5%	384 73.6%	1934 73.7%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.
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.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	525	524	526	521	522
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.133 (0.008)	0.148 (0.008)	0.139 (0.008)	0.241 (0.008)	0.256 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.123
	Confidence Interval	(2-Sided) 95%; 0.100 to 0.146
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.117
	Confidence Interval	95%; 0.094 to 0.140
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.109
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.132
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.093
	Confidence Interval	(2-Sided) 95%; 0.070 to 0.116
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.102
	Confidence Interval	(2-Sided) 95%; 0.080 to 0.125
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2169
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.037
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.130
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5849
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.017 to 0.029
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1863
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.039
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4352
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.032 to 0.014
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

2. Primary Outcome

Title	Trough FEV1 Response on Day 170.
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

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	519	519	520	518	521
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.054 (0.009)	0.083 (0.008)	0.065 (0.008)	0.111 (0.008)	0.136 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.059 to 0.106
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95%; 0.047 to 0.094
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.058
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.081
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0174
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.052
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.046
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.070
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0407
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; 0.001 to 0.048
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.053
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.077
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3326
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.035
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0151
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.006 to 0.053
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1421
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.018
	Confidence Interval	(2-Sided) 95%; -0.041 to 0.006
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

3. Primary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	954	960	954	990	979
Least Squares Mean (Standard Error); Unit of Measure: points on a scale
	38.366 (0.396)	37.792 (0.390)	37.907 (0.393)	37.335 (0.385)	36.674 (0.386)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0022
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.693
	Confidence Interval	(2-Sided) 95%; -2.778 to -0.608
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.553
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0252
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.233
	Confidence Interval	(2-Sided) 95%; -2.313 to -0.153
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.551
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0620
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.031
	Confidence Interval	(2-Sided) 95%; -2.113 to 0.052
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.552
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4051
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.456
	Confidence Interval	(2-Sided) 95%; -1.531 to 0.618
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.548
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2988
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.571
	Confidence Interval	(2-Sided) 95%; -1.649 to 0.507
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.550
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2249
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.662
	Confidence Interval	(2-Sided) 95%; -1.731 to 0.407
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.545
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0418
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.118
	Confidence Interval	(2-Sided) 95%; -2.195 to -0.042
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.549
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4097
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.460
	Confidence Interval	(2-Sided) 95%; -1.552 to 0.633
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.557
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg) Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3013
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.575
	Confidence Interval	(2-Sided) 95%; -1.664 to 0.515
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.556
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8355
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.115
	Confidence Interval	(2-Sided) 95%; -0.970 to 1.200
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.554
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

4. Secondary Outcome

Title	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) is the key secondary endpoint. The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Time Frame	Day 169

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	984	982	978	992	992
Least Squares Mean (Standard Error); Unit of Measure: points on a scale
	1.564 (0.096)	1.690 (0.095)	1.627 (0.096)	1.980 (0.095)	1.983 (0.095)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0019
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.420
	Confidence Interval	(2-Sided) 95%; 0.155 to 0.684
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0082
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.356
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.619
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0020
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.416
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.681
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0307
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.290
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.554
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.134
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0088
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.352
	Confidence Interval	(2-Sided) 95%; 0.089 to 0.616
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9801
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.003
	Confidence Interval	(2-Sided) 95%; -0.259 to 0.266
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.134
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0289
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.294
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.557
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.134
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6382
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; -0.202 to 0.330
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.136
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3525
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.126
	Confidence Interval	(2-Sided) 95%; -0.140 to 0.391
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6457
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.062
	Confidence Interval	(2-Sided) 95%; -0.327 to 0.203
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.135
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

5. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 1
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.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	525	524	526	521	522
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.205 (0.009)	0.148 (0.009)	0.157 (0.009)	0.226 (0.009)	0.237 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0067
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.056
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.081
	Confidence Interval	(2-Sided) 95%; 0.057 to 0.104
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0746
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.022
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.045
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.078
	Confidence Interval	(2-Sided) 95%; 0.054 to 0.101
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.070
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.093
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3549
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.011
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.035
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.089
	Confidence Interval	(2-Sided) 95%; 0.065 to 0.113
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.048
	Confidence Interval	(2-Sided) 95%; -0.072 to -0.025
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.056
	Confidence Interval	(2-Sided) 95%; -0.080 to -0.033
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5018
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.008
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.032
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

6. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 85
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.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	525	524	526	521	522
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.161 (0.009)	0.176 (0.009)	0.162 (0.009)	0.271 (0.009)	0.289 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.128
	Confidence Interval	(2-Sided) 95%; 0.104 to 0.152
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.126
	Confidence Interval	(2-Sided) 95%; 0.102 to 0.150
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.087 to 0.135
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.096
	Confidence Interval	(2-Sided) 95%; 0.072 to 0.120
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.109
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.133
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1569
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.041
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.113
	Confidence Interval	(2-Sided) 95%; 0.089 to 0.137
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8834
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.002
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.026
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2129
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.039
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2702
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.013
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.010
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

7. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 365
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.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	525	524	526	521	522
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.096 (0.009)	0.116 (0.009)	0.122 (0.009)	0.214 (0.009)	0.237 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.141
	Confidence Interval	(2-Sided) 95%; 0.117 to 0.166
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.115
	Confidence Interval	(2-Sided) 95%; 0.090 to 0.139
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.119
	Confidence Interval	(2-Sided) 95%; 0.094 to 0.143
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.099
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.123
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; 0.067 to 0.117
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0717
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.023
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.047
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.121
	Confidence Interval	(2-Sided) 95%; 0.097 to 0.146
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0344
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.027
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.051
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1126
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.045
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6009
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.031
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

8. Secondary Outcome

Title	Trough FEV1 Response on Day 15.
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

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	519	519	520	518	521
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.085 (0.009)	0.101 (0.009)	0.094 (0.009)	0.132 (0.009)	0.157 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95%; 0.049 to 0.096
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.087
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.070
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0122
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.030
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0021
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.061
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0347
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.049
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.056
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.080
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4407
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.033
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1777
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.040
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5641
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.017
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

9. Secondary Outcome

Title	Trough FEV1 Response on Day 43
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.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	519	519	520	518	521
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.083 (0.009)	0.097 (0.009)	0.088 (0.009)	0.120 (0.009)	0.163 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95%; 0.057 to 0.104
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.099
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0018
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.062
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0517
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; -0.000 to 0.047
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0072
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.056
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.066
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.066
	Confidence Interval	(2-Sided) 95%; 0.042 to 0.090
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6619
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.005
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.029
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2401
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.038
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4601
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.033 to 0.015
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

10. Secondary Outcome

Title	Trough FEV1 Response on Day 85
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85.

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	519	519	520	518	521
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.057 (0.009)	0.077 (0.009)	0.070 (0.009)	0.128 (0.009)	0.146 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; 0.064 to 0.112
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.100
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.070
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.094
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.075
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.058
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.082
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1405
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.042
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; 0.045 to 0.093
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3118
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.036
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1171
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.019
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.043
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5759
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.017
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

11. Secondary Outcome

Title	Trough FEV1 Response on Day 169
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169

Outcome Measure Data

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)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Number of Participants Analyzed	519	519	520	518	521
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.033 (0.009)	0.047 (0.009)	0.050 (0.009)	0.094 (0.009)	0.112 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.103
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.062
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.086
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.085
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; 0.022 to 0.071
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.068
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6 <

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