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

• ClinicalTrials.gov Identifier: NCT01431287
• Recruitment Status: Completed
• First Posted: September 9, 2011
• Results First Posted: July 16, 2015
• Last Update Posted: July 16, 2015
• Sponsor: 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: 2539

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	510 [1]	507	507	508	507
Completed	412	409	410	445	430
Not Completed	98	98	97	63	77
Reason Not Completed
not treated	0	0	1	0	0
Adverse Event	59	57	53	33	41
Non compliant with protocol	6	6	5	6	5
Lost to Follow-up	0	3	2	3	1
Consent withdrawn not due to AE	29	30	34	19	29
not stated above	4	2	2	2	1
[1] started are actually the randomized

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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Total of all reporting groups
Overall Number of Baseline Participants		510	507	506	508	507	2538
Baseline Analysis Population Description		Treated set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	510 participants	507 participants	506 participants	508 participants	507 participants	2538 participants
		64.7 (8.3)	63.9 (8.7)	63.5 (8.7)	64.1 (7.6)	62.7 (8.4)	63.8 (8.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	510 participants	507 participants	506 participants	508 participants	507 participants	2538 participants
	Female	132 25.9%	146 28.8%	134 26.5%	140 27.6%	158 31.2%	710 28.0%
	Male	378 74.1%	361 71.2%	372 73.5%	368 72.4%	349 68.8%	1828 72.0%

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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	507	504	500	506	502
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.136 (0.009)	0.125 (0.009)	0.165 (0.009)	0.256 (0.009)	0.268 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.132
	Confidence Interval	(2-Sided) 95%; 0.108 to 0.157
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.103
	Confidence Interval	(2-Sided) 95%; 0.078 to 0.127
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.121
	Confidence Interval	(2-Sided) 95%; 0.096 to 0.145
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.131
	Confidence Interval	(2-Sided) 95%; 0.106 to 0.155
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.091
	Confidence Interval	(2-Sided) 95%; 0.066 to 0.115
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3394
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.036
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.143
	Confidence Interval	(2-Sided) 95%; 0.118 to 0.167
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0173
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.030
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4210
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.010
	Confidence Interval	(2-Sided) 95%; -0.035 to 0.014
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0014
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.040
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.064
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.012
	Estimation Comments	spatial power covariance structure for within-patient errors

2. Primary Outcome

Title	Trough FEV1 Response on Day 170
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	503	499	498	500	497
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.057 (0.009)	0.062 (0.009)	0.096 (0.009)	0.125 (0.009)	0.145 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; 0.063 to 0.113
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.075
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.067
	Confidence Interval	(2-Sided) 95%; 0.042 to 0.092
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.062
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.087
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0231
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1073
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.021
	Confidence Interval	(2-Sided) 95%; -0.004 to 0.046
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.058 to 0.108
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0029
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 95%; 0.013 to 0.063
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6939
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.005
	Confidence Interval	(2-Sided) 95%; -0.020 to 0.030
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0097
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.058
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

3. Primary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	954	960	954	990	979
Least Squares Mean (Standard Error); Unit of Measure: points on a scale
	38.366 (0.396)	37.792 (0.390)	37.907 (0.393)	37.335 (0.385)	36.674 (0.386)

Statistical Analysis 1

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

Statistical Analysis 2

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

Statistical Analysis 3

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

Statistical Analysis 4

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

Statistical Analysis 5

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

Statistical Analysis 6

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

Statistical Analysis 7

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

Statistical Analysis 8

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

Statistical Analysis 9

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

Statistical Analysis 10

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

4. Secondary Outcome

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

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

Statistical Analysis 1

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

Statistical Analysis 2

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

Statistical Analysis 3

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

Statistical Analysis 4

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

Statistical Analysis 5

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

Statistical Analysis 6

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

Statistical Analysis 7

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

Statistical Analysis 8

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

Statistical Analysis 9

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

Statistical Analysis 10

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

5. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 1
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	507	504	500	506	502
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.196 (0.009)	0.135 (0.009)	0.164 (0.009)	0.228 (0.009)	0.229 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0095
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.058
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; 0.040 to 0.090
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0112
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.058
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.093
	Confidence Interval	(2-Sided) 95%; 0.068 to 0.119
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.090
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9514
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95%; -0.024 to 0.026
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 95%; 0.069 to 0.119
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0131
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.032
	Confidence Interval	(2-Sided) 95%; -0.057 to -0.007
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.061
	Confidence Interval	(2-Sided) 95%; -0.086 to -0.036
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0243
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

6. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 85
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 (on day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Arm/Group Description:	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	507	504	500	506	502
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.153 (0.009)	0.165 (0.009)	0.187 (0.009)	0.272 (0.009)	0.297 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.145
	Confidence Interval	(2-Sided) 95%; 0.119 to 0.170
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.136
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.119
	Confidence Interval	(2-Sided) 95%; 0.094 to 0.144
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.106
	Confidence Interval	(2-Sided) 95%; 0.081 to 0.132
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.085
	Confidence Interval	(2-Sided) 95%; 0.059 to 0.110
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0470
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95%; 0.000 to 0.051
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.132
	Confidence Interval	(2-Sided) 95%; 0.107 to 0.158
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0083
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.060
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3329
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.013
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.038
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0958
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.022
	Confidence Interval	(2-Sided) 95%; -0.004 to 0.047
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

7. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 365
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	507	504	500	506	502
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.105 (0.010)	0.105 (0.010)	0.124 (0.010)	0.223 (0.009)	0.237 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.132
	Confidence Interval	(2-Sided) 95%; 0.105 to 0.158
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.112
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.139
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.118
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.144
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.118
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.144
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95%; 0.072 to 0.125
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3008
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.040
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.132
	Confidence Interval	(2-Sided) 95%; 0.105 to 0.158
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1484
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.046
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9981
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.027
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1480
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.046
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

8. Secondary Outcome

Title	Trough FEV1 Response on Day 15
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	503	499	498	500	497
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.083 (0.009)	0.085 (0.009)	0.112 (0.009)	0.147 (0.009)	0.148 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; 0.040 to 0.090
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0050
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.036
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.061
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.089
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.088
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0057
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.036
	Confidence Interval	(2-Sided) 95%; 0.010 to 0.061
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9633
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.026
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.088
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0250
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8949
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.002
	Confidence Interval	(2-Sided) 95%; -0.023 to 0.027
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0351
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.027
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.052
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

9. Secondary Outcome

Title	Trough FEV1 Response on Day 43
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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	503	499	498	500	497
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.070 (0.009)	0.085 (0.009)	0.103 (0.009)	0.146 (0.009)	0.150 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.105
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; 0.022 to 0.073
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.101
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; 0.036 to 0.086
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0007
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; 0.018 to 0.069
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7755
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.004
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.029
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.090
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0118
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.058
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2416
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.040
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1792
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.043
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	Spatial power covariance structure for within-patient errors.

10. Secondary Outcome

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

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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	503	499	498	500	497
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.047 (0.009)	0.081 (0.009)	0.088 (0.009)	0.129 (0.009)	0.147 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.100
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.125
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; 0.033 to 0.084
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.057 to 0.107
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.073
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0014
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.067
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1747
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.043
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; 0.040 to 0.091
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0016
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.066
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0081
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.060
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6110
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.032
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

11. Secondary Outcome

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

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 in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Overall Number of Participants Analyzed	503	499	498	500	497
Least Squares Mean (Standard Error); Unit of Measure: Litres
	0.034 (0.009)	0.041 (0.009)	0.068 (0.009)	0.111 (0.009)	0.119 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.085
	Confidence Interval	(2-Sided) 95%; 0.059 to 0.111
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.076
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.077
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.102
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; 0.044 to 0.095
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0013
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.068
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5274
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.008
	Confidence Interval	(2-Sided) 95%; -0.017 to 0.034
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.078
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.103
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0083
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.035
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.060
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors