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

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT01431287

Collaborator

(none)

2,539

Enrollment

240

Locations

Arms

Duration (Months)

10.6

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The overall objective of this study is to assess the efficacy and safety of 52 weeks once daily treatment with orally inhaled tiotropium + olodaterol FDC (delivered by the RESPIMAT Inhaler) compared with the individual components (tiotropium, olodaterol) (delivered by the RESPIMAT Inhaler) in patients with COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: tiotropium + olodaterol Drug: tiotropium + olodaterol Drug: tiotropium Drug: tiotropium Drug: olodaterol Device: Respimat	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

2539 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

Primary Purpose:

Treatment

Official Title:

A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compared With the Individual Components (2.5 µg and 5 µg Tiotropium, 5 µg Olodaterol) (Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD) [TOnado TM 2]

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Nov 1, 2013

Actual Study Completion Date :

Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: tiotropium+olodaterol high dose FDC Once daily 2 puffs solution for inhalation Respimat	Drug: tiotropium + olodaterol fixed dose combination Device: Respimat Respimat inhaler
Experimental: tiotropium+olodaterol low dose FDC Once daily 2 puffs solution for inhalation Respimat	Drug: tiotropium + olodaterol fixed dose combination Device: Respimat Respimat inhaler
Active Comparator: olodaterol Once daily 2 puffs solution for inhalation Respimat	Drug: olodaterol one dose only Device: Respimat Respimat inhaler
Active Comparator: tiotropium low dose Once daily 2 puffs solution for inhalation Respimat	Drug: tiotropium low dose or high dose Device: Respimat Respimat inhaler
Active Comparator: tiotropium high dose Once daily 2 puffs solution for inhalation Respimat	Drug: tiotropium low dose or high dose Device: Respimat Respimat inhaler

Outcome Measures

Primary Outcome Measures

Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169 [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]
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.
Trough FEV1 Response on Day 170 [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]
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.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). [Day 169]
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.

Secondary Outcome Measures

Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 169]
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.
FEV1 AUC(0-3h) Response on Day 1 [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]
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.
FEV1 AUC(0-3h) Response on Day 85 [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]
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.
FEV1 AUC(0-3h) Response on Day 365 [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]
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.
Trough FEV1 Response on Day 15 [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]
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.
Trough FEV1 Response on Day 43 [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]
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.
Trough FEV1 Response on Day 85 [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]
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.
Trough FEV1 Response on Day 169 [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]
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.
Trough FEV1 Response on Day 365 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365]
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.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1 [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]
FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.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 mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85 [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]
FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.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 mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169 [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]
FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. 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 mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365 [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]
FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. 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 mixed effect repeated measures (MMRM) model in each treatment group.
Trough FVC Response on Day 15 [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]
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
Trough FVC Response on Day 43 [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]
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
Trough FVC Response on Day 85 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85]
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
Trough FVC Response on Day 170 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23h and at 23h 50 min after inhalation of study medication on day 170]
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day. Trough FVC response was defined as trough FVC minus baseline FVC. 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.
Trough FVC Response on Day 365 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365]
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169]
FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169]
FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169]
FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169]
FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 85]
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.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 365]
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.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 43]
Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 85]
Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) [Day 365]
Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Diagnosis of chronic obstructive pulmonary disease.
Relatively stable airway obstruction with post FEV1< 80% predicted normal and post FEV1/FVC <70%.
Male or female patients, 40 years of age or older.
Smoking history of more than 10 pack years.

Exclusion criteria:

Significant disease other than COPD
Clinically relevant abnormal lab values.
History of asthma.
Diagnosis of thyrotoxicosis
Diagnosis of paroxysmal tachycardia
History of myocardial infarction within 1 year of screening visit
Unstable or life-threatening cardiac arrhythmia.
Hospitalization for heart failure within the past year.
Known active tuberculosis.
Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years
History of life-threatening pulmonary obstruction.
History of cystic fibrosis.
Clinically evident bronchiectasis.
History of significant alcohol or drug abuse.
Thoracotomy with pulmonary resection
Oral ß-adrenergics.
Oral corticosteroid medication at unstable doses
Regular use of daytime oxygen therapy for more than one hour per day
Pulmonary rehabilitation program in the six weeks prior to the screening visit
Investigational drug within one month or six half lives (whichever is greater) prior to screening visit
Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA
Pregnant or nursing women.
Women of childbearing potential not using a highly effective method of birth control
Patients who are unable to comply with pulmonary medication restrictions

Contacts and Locations

Locations

	Site	City	State	Country
1	1237.6.01106 Boehringer Ingelheim Investigational Site	Greer	California	United States
2	1237.6.01120 Boehringer Ingelheim Investigational Site	Fort Collins	Colorado	United States
3	1237.6.01131 Boehringer Ingelheim Investigational Site	Danbury	Connecticut	United States
4	1237.6.01117 Boehringer Ingelheim Investigational Site	Waterbury	Connecticut	United States
5	1237.6.01118 Boehringer Ingelheim Investigational Site	Deland	Florida	United States
6	1237.6.01126 Boehringer Ingelheim Investigational Site	Tampa	Florida	United States
7	1237.6.01109 Boehringer Ingelheim Investigational Site	Winter Park	Florida	United States
8	1237.6.01134 Boehringer Ingelheim Investigational Site	Atlanta	Georgia	United States
9	1237.6.01107 Boehringer Ingelheim Investigational Site	Couer d'Alene	Idaho	United States
10	1237.6.01110 Boehringer Ingelheim Investigational Site	Lafayette	Louisiana	United States
11	1237.6.01128 Boehringer Ingelheim Investigational Site	Baltimore	Maryland	United States
12	1237.6.01130 Boehringer Ingelheim Investigational Site	North Dartmouth	Massachusetts	United States
13	1237.6.01104 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota	United States
14	1237.6.01116 Boehringer Ingelheim Investigational Site	Plymouth	Minnesota	United States
15	1237.6.01121 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
16	1237.6.01123 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
17	1237.6.01129 Boehringer Ingelheim Investigational Site	Henderson	Nevada	United States
18	1237.6.01136 Boehringer Ingelheim Investigational Site	Marlton	New Jersey	United States
19	1237.6.01108 Boehringer Ingelheim Investigational Site	Albuquerque	New Mexico	United States
20	1237.6.01127 Boehringer Ingelheim Investigational Site	Bayside	New York	United States
21	1237.6.01139 Boehringer Ingelheim Investigational Site	Great Neck	New York	United States
22	1237.6.01135 Boehringer Ingelheim Investigational Site	Charlotte	North Carolina	United States
23	1237.6.01114 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
24	1237.6.01102 Boehringer Ingelheim Investigational Site	Columbus	Ohio	United States
25	1237.6.01115 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
26	1237.6.01101 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania	United States
27	1237.6.01113 Boehringer Ingelheim Investigational Site	East Providence	Rhode Island	United States
28	1237.6.01122 Boehringer Ingelheim Investigational Site	Charleston	South Carolina	United States
29	1237.6.01132 Boehringer Ingelheim Investigational Site	Greenville	South Carolina	United States
30	1237.6.01137 Boehringer Ingelheim Investigational Site	Greenville	South Carolina	United States
31	1237.6.01111 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina	United States
32	1237.6.01105 Boehringer Ingelheim Investigational Site	Union	South Carolina	United States
33	1237.6.01138 Boehringer Ingelheim Investigational Site	Killeen	Texas	United States
34	1237.6.01124 Boehringer Ingelheim Investigational Site	McKinney	Texas	United States
35	1237.6.01112 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
36	1237.6.01133 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
37	1237.6.01125 Boehringer Ingelheim Investigational Site	Spokane	Washington	United States
38	1237.6.01103 Boehringer Ingelheim Investigational Site	Tacoma	Washington	United States
39	1237.6.43006 Boehringer Ingelheim Investigational Site	Feldbach		Austria
40	1237.6.43005 Boehringer Ingelheim Investigational Site	Gänserndorf		Austria
41	1237.6.43002 Boehringer Ingelheim Investigational Site	Innsbruck		Austria
42	1237.6.43004 Boehringer Ingelheim Investigational Site	Leoben		Austria
43	1237.6.43001 Boehringer Ingelheim Investigational Site	Linz		Austria
44	1237.6.43003 Boehringer Ingelheim Investigational Site	Salzburg		Austria
45	1237.6.32007 Boehringer Ingelheim Investigational Site	Brussel		Belgium
46	1237.6.32005 Boehringer Ingelheim Investigational Site	Bruxelles		Belgium
47	1237.6.32004 Boehringer Ingelheim Investigational Site	Gent		Belgium
48	1237.6.32002 Boehringer Ingelheim Investigational Site	Jambes		Belgium
49	1237.6.32009 Boehringer Ingelheim Investigational Site	Lebbeke		Belgium
50	1237.6.32001 Boehringer Ingelheim Investigational Site	Leuven		Belgium
51	1237.6.32006 Boehringer Ingelheim Investigational Site	Liège		Belgium
52	1237.6.32008 Boehringer Ingelheim Investigational Site	Oostende		Belgium
53	1237.6.32010 Boehringer Ingelheim Investigational Site	Turnhout		Belgium
54	1237.6.55013 Boehringer Ingelheim Investigational Site	Botucatu		Brazil
55	1237.6.55010 Boehringer Ingelheim Investigational Site	Florianopolis		Brazil
56	1237.6.55012 Boehringer Ingelheim Investigational Site	Passo Fundo		Brazil
57	1237.6.55001 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
58	1237.6.55002 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
59	1237.6.55003 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
60	1237.6.55005 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
61	1237.6.55009 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
62	1237.6.55006 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
63	1237.6.55007 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
64	1237.6.55011 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
65	1237.6.02109 Boehringer Ingelheim Investigational Site	Edmonton	Alberta	Canada
66	1237.6.02111 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia	Canada
67	1237.6.02106 Boehringer Ingelheim Investigational Site	Moncton	New Brunswick	Canada
68	1237.6.02110 Boehringer Ingelheim Investigational Site	Courtice	Ontario	Canada
69	1237.6.02101 Boehringer Ingelheim Investigational Site	Downsview	Ontario	Canada
70	1237.6.02112 Boehringer Ingelheim Investigational Site	Sarnia	Ontario	Canada
71	1237.6.02103 Boehringer Ingelheim Investigational Site	Toronto	Ontario	Canada
72	1237.6.02102 Boehringer Ingelheim Investigational Site	Windsor	Ontario	Canada
73	1237.6.02104 Boehringer Ingelheim Investigational Site	Point Claire	Quebec	Canada
74	1237.6.02105 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec	Canada
75	1237.6.02108 Boehringer Ingelheim Investigational Site	Ste-Foy	Quebec	Canada
76	1237.6.86117 Boehringer Ingelheim Investigational Site	Baotou		China
77	1237.6.86102 Boehringer Ingelheim Investigational Site	Beijing		China
78	1237.6.86104 Boehringer Ingelheim Investigational Site	Beijing		China
79	1237.6.86105 Boehringer Ingelheim Investigational Site	Beijing		China
80	1237.6.86115 Boehringer Ingelheim Investigational Site	Changsha		China
81	1237.6.86110 Boehringer Ingelheim Investigational Site	Chengdu		China
82	1237.6.86111 Boehringer Ingelheim Investigational Site	Chongqing		China
83	1237.6.86109 Boehringer Ingelheim Investigational Site	Haikou		China
84	1237.6.86108 Boehringer Ingelheim Investigational Site	Hangzhou		China
85	1237.6.86116 Boehringer Ingelheim Investigational Site	Hohhot		China
86	1237.6.86114 Boehringer Ingelheim Investigational Site	Jinan		China
87	1237.6.86106 Boehringer Ingelheim Investigational Site	Nanjing		China
88	1237.6.86101 Boehringer Ingelheim Investigational Site	Shanghai		China
89	1237.6.86113 Boehringer Ingelheim Investigational Site	Shenyang		China
90	1237.6.86107 Boehringer Ingelheim Investigational Site	Suzhou		China
91	1237.6.86112 Boehringer Ingelheim Investigational Site	Xi'An		China
92	1237.6.57001 Boehringer Ingelheim Investigational Site	Bogota DC		Colombia
93	1237.6.57003 Boehringer Ingelheim Investigational Site	Bogota DC		Colombia
94	1237.6.57007 Boehringer Ingelheim Investigational Site	Bogota DC		Colombia
95	1237.6.57008 Boehringer Ingelheim Investigational Site	Bogota		Colombia
96	1237.6.57006 Boehringer Ingelheim Investigational Site	Cali		Colombia
97	1237.6.57004 Boehringer Ingelheim Investigational Site	Floridablanca		Colombia
98	1237.6.38503 Boehringer Ingelheim Investigational Site	Petrinja		Croatia
99	1237.6.38504 Boehringer Ingelheim Investigational Site	Rijeka		Croatia
100	1237.6.38502 Boehringer Ingelheim Investigational Site	Zadar		Croatia
101	1237.6.38501 Boehringer Ingelheim Investigational Site	Zagreb		Croatia
102	1237.6.49022 Boehringer Ingelheim Investigational Site	Aschaffenburg		Germany
103	1237.6.49017 Boehringer Ingelheim Investigational Site	Berlin		Germany
104	1237.6.49026 Boehringer Ingelheim Investigational Site	Frankfurt		Germany
105	1237.6.49027 Boehringer Ingelheim Investigational Site	Frankfurt		Germany
106	1237.6.49025 Boehringer Ingelheim Investigational Site	Großhansdorf		Germany
107	1237.6.49016 Boehringer Ingelheim Investigational Site	Halle		Germany
108	1237.6.49024 Boehringer Ingelheim Investigational Site	Hamburg		Germany
109	1237.6.49021 Boehringer Ingelheim Investigational Site	Hannover		Germany
110	1237.6.49019 Boehringer Ingelheim Investigational Site	Leipzig		Germany
111	1237.6.49028 Boehringer Ingelheim Investigational Site	Mainz		Germany
112	1237.6.49018 Boehringer Ingelheim Investigational Site	Rodgau/Dudenhofen		Germany
113	1237.6.49020 Boehringer Ingelheim Investigational Site	Schwerin		Germany
114	1237.6.49023 Boehringer Ingelheim Investigational Site	Teuchern		Germany
115	1237.6.36001 Boehringer Ingelheim Investigational Site	Debrecen		Hungary
116	1237.6.36004 Boehringer Ingelheim Investigational Site	Gödöllö		Hungary
117	1237.6.36005 Boehringer Ingelheim Investigational Site	Pecs		Hungary
118	1237.6.36003 Boehringer Ingelheim Investigational Site	Sopron		Hungary
119	1237.6.36002 Boehringer Ingelheim Investigational Site	Szeged		Hungary
120	1237.6.91003 Boehringer Ingelheim Investigational Site	Chennai		India
121	1237.6.91011 Boehringer Ingelheim Investigational Site	Coimbatore		India
122	1237.6.91004 Boehringer Ingelheim Investigational Site	Jaipur		India
123	1237.6.91002 Boehringer Ingelheim Investigational Site	Kolkatta		India
124	1237.6.91007 Boehringer Ingelheim Investigational Site	Maharastra		India
125	1237.6.91006 Boehringer Ingelheim Investigational Site	Mumbai		India
126	1237.6.91009 Boehringer Ingelheim Investigational Site	Nashik, Maharashtra		India
127	1237.6.91008 Boehringer Ingelheim Investigational Site	Pune		India
128	1237.6.35304 Boehringer Ingelheim Investigational Site	County Limerick		Ireland
129	1237.6.35303 Boehringer Ingelheim Investigational Site	Dublin 24		Ireland
130	1237.6.35301 Boehringer Ingelheim Investigational Site	Dublin 4		Ireland
131	1237.6.81127 Boehringer Ingelheim Investigational Site	Abeno-ku, Osaka, Osaka		Japan
132	1237.6.81123 Boehringer Ingelheim Investigational Site	Aoi-ku, Shizuoka, Shizuoka		Japan
133	1237.6.81132 Boehringer Ingelheim Investigational Site	Chuo-ku, Kobe, Hyogo		Japan
134	1237.6.81121 Boehringer Ingelheim Investigational Site	Fukui, Fukui		Japan
135	1237.6.81137 Boehringer Ingelheim Investigational Site	Fukuyama, Hiroshima		Japan
136	1237.6.81109 Boehringer Ingelheim Investigational Site	Hachioji, Tokyo		Japan
137	1237.6.81134 Boehringer Ingelheim Investigational Site	Himeji, Hyogo		Japan
138	1237.6.81106 Boehringer Ingelheim Investigational Site	Hitachi, Ibaraki		Japan
139	1237.6.81139 Boehringer Ingelheim Investigational Site	Iizuka, Fukuoka		Japan
140	1237.6.81102 Boehringer Ingelheim Investigational Site	Iwamizawa, Hokkaido		Japan
141	1237.6.81117 Boehringer Ingelheim Investigational Site	Kamakura, Kanagawa		Japan
142	1237.6.81120 Boehringer Ingelheim Investigational Site	Kanazawa, Ishikawa		Japan
143	1237.6.81113 Boehringer Ingelheim Investigational Site	Kanazawa, Yokohama, Kanagawa		Japan
144	1237.6.81108 Boehringer Ingelheim Investigational Site	Kashiwa, Chiba		Japan
145	1237.6.81114 Boehringer Ingelheim Investigational Site	Kawasaki-ku, Kawasaki, Kanagawa		Japan
146	1237.6.81135 Boehringer Ingelheim Investigational Site	Kita-ku, Okayama, Okayama		Japan
147	1237.6.81126 Boehringer Ingelheim Investigational Site	Kita-ku, Sakai, Osaka		Japan
148	1237.6.81101 Boehringer Ingelheim Investigational Site	Kita-ku, Sapporo, Hokkaido		Japan
149	1237.6.81136 Boehringer Ingelheim Investigational Site	Kurashiki, Okayama		Japan
150	1237.6.81116 Boehringer Ingelheim Investigational Site	Minami-ku, Yokohama, Kanagawa		Japan
151	1237.6.81118 Boehringer Ingelheim Investigational Site	Minami-ku, Yokohama, Kanagawa		Japan
152	1237.6.81112 Boehringer Ingelheim Investigational Site	Mitaka, Tokyo		Japan
153	1237.6.81105 Boehringer Ingelheim Investigational Site	Mito, Ibaraki		Japan
154	1237.6.81142 Boehringer Ingelheim Investigational Site	Naha, Okinawa		Japan
155	1237.6.81131 Boehringer Ingelheim Investigational Site	Nishi-ku, Kobe, Hyogo		Japan
156	1237.6.81104 Boehringer Ingelheim Investigational Site	Obihiro, Hokkaido		Japan
157	1237.6.81141 Boehringer Ingelheim Investigational Site	Okinawa, Okinawa		Japan
158	1237.6.81110 Boehringer Ingelheim Investigational Site	Ota-ku, Tokyo		Japan
159	1237.6.81138 Boehringer Ingelheim Investigational Site	Sakaide, Kagawa		Japan
160	1237.6.81103 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido		Japan
161	1237.6.81140 Boehringer Ingelheim Investigational Site	Shimajiri-gun, Okinawa		Japan
162	1237.6.81144 Boehringer Ingelheim Investigational Site	Shimajiri-gun, Okinawa		Japan
163	1237.6.81111 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo		Japan
164	1237.6.81145 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo		Japan
165	1237.6.81107 Boehringer Ingelheim Investigational Site	Soka, Saitama		Japan
166	1237.6.81133 Boehringer Ingelheim Investigational Site	Takarazuka, Hyogo		Japan
167	1237.6.81122 Boehringer Ingelheim Investigational Site	Takayama, Gifu		Japan
168	1237.6.81143 Boehringer Ingelheim Investigational Site	Tomigusuku, Okinawa		Japan
169	1237.6.81128 Boehringer Ingelheim Investigational Site	Toyonaka, Osaka		Japan
170	1237.6.81124 Boehringer Ingelheim Investigational Site	Uji, Kyoto		Japan
171	1237.6.81130 Boehringer Ingelheim Investigational Site	Yabu, Hyogo		Japan
172	1237.6.81129 Boehringer Ingelheim Investigational Site	Yao, Osaka		Japan
173	1237.6.81119 Boehringer Ingelheim Investigational Site	Yokosuka, Kanagawa		Japan
174	1237.6.47005 Boehringer Ingelheim Investigational Site	Elverum		Norway
175	1237.6.47001 Boehringer Ingelheim Investigational Site	Hønefoss		Norway
176	1237.6.47002 Boehringer Ingelheim Investigational Site	Kløfta		Norway
177	1237.6.47004 Boehringer Ingelheim Investigational Site	Lierskogen		Norway
178	1237.6.47003 Boehringer Ingelheim Investigational Site	Oslo		Norway
179	1237.6.47007 Boehringer Ingelheim Investigational Site	SKI		Norway
180	1237.6.47008 Boehringer Ingelheim Investigational Site	Svelvik		Norway
181	1237.6.40004 Boehringer Ingelheim Investigational Site	Arad		Romania
182	1237.6.40005 Boehringer Ingelheim Investigational Site	Arad		Romania
183	1237.6.40001 Boehringer Ingelheim Investigational Site	Bucharest		Romania
184	1237.6.40002 Boehringer Ingelheim Investigational Site	Bucuresti		Romania
185	1237.6.40003 Boehringer Ingelheim Investigational Site	Cluj		Romania
186	1237.6.07004 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
187	1237.6.07005 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
188	1237.6.07002 Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
189	1237.6.07003 Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
190	1237.6.07001 Boehringer Ingelheim Investigational Site	Yaroslavl		Russian Federation
191	1237.6.38103 Boehringer Ingelheim Investigational Site	Belgrade		Serbia
192	1237.6.38104 Boehringer Ingelheim Investigational Site	Belgrade		Serbia
193	1237.6.38105 Boehringer Ingelheim Investigational Site	Belgrade		Serbia
194	1237.6.38102 Boehringer Ingelheim Investigational Site	Kragujevac		Serbia
195	1237.6.38101 Boehringer Ingelheim Investigational Site	Nis		Serbia
196	1237.6.42101 Boehringer Ingelheim Investigational Site	Bardejov		Slovakia
197	1237.6.42102 Boehringer Ingelheim Investigational Site	Bojnice		Slovakia
198	1237.6.42104 Boehringer Ingelheim Investigational Site	Kosice		Slovakia
199	1237.6.42107 Boehringer Ingelheim Investigational Site	Nitra		Slovakia
200	1237.6.42103 Boehringer Ingelheim Investigational Site	Spisska Nova Ves		Slovakia
201	1237.6.42106 Boehringer Ingelheim Investigational Site	Zilina		Slovakia
202	1237.6.27002 Boehringer Ingelheim Investigational Site	Bellville		South Africa
203	1237.6.27001 Boehringer Ingelheim Investigational Site	Cape Town		South Africa
204	1237.6.27003 Boehringer Ingelheim Investigational Site	Cape Town		South Africa
205	1237.6.27004 Boehringer Ingelheim Investigational Site	Cape Town		South Africa
206	1237.6.27005 Boehringer Ingelheim Investigational Site	Pretoria		South Africa
207	1237.6.34008 Boehringer Ingelheim Investigational Site	Badalona (Barcelona)		Spain
208	1237.6.34003 Boehringer Ingelheim Investigational Site	Barcelona		Spain
209	1237.6.34009 Boehringer Ingelheim Investigational Site	Barcelona		Spain
210	1237.6.34001 Boehringer Ingelheim Investigational Site	Hospitalet de Llobregat		Spain
211	1237.6.34002 Boehringer Ingelheim Investigational Site	Mérida		Spain
212	1237.6.34005 Boehringer Ingelheim Investigational Site	Pozuelo de Alarcón		Spain
213	1237.6.34004 Boehringer Ingelheim Investigational Site	San Juan de Alicante		Spain
214	1237.6.34006 Boehringer Ingelheim Investigational Site	Vic (Barcelona)		Spain
215	1237.6.46003 Boehringer Ingelheim Investigational Site	Boden		Sweden
216	1237.6.46002 Boehringer Ingelheim Investigational Site	Göteborg		Sweden
217	1237.6.46006 Boehringer Ingelheim Investigational Site	Härnösand		Sweden
218	1237.6.46005 Boehringer Ingelheim Investigational Site	Höllviken		Sweden
219	1237.6.46001 Boehringer Ingelheim Investigational Site	Lund		Sweden
220	1237.6.46004 Boehringer Ingelheim Investigational Site	Stockholm		Sweden
221	1237.6.46007 Boehringer Ingelheim Investigational Site	Uddevalla		Sweden
222	1237.6.88607 Boehringer Ingelheim Investigational Site	Kaohsiung City		Taiwan
223	1237.6.88608 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
224	1237.6.88602 Boehringer Ingelheim Investigational Site	New Taipei City		Taiwan
225	1237.6.88604 Boehringer Ingelheim Investigational Site	Taichung		Taiwan
226	1237.6.88605 Boehringer Ingelheim Investigational Site	Tainan		Taiwan
227	1237.6.88601 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
228	1237.6.88603 Boehringer Ingelheim Investigational Site	Taoyuan County		Taiwan
229	1237.6.90105 Boehringer Ingelheim Investigational Site	Ankara		Turkey
230	1237.6.90103 Boehringer Ingelheim Investigational Site	Denizli		Turkey
231	1237.6.90104 Boehringer Ingelheim Investigational Site	Istanbul		Turkey
232	1237.6.90101 Boehringer Ingelheim Investigational Site	Izmir		Turkey
233	1237.6.90102 Boehringer Ingelheim Investigational Site	Izmir		Turkey
234	1237.6.44002 Boehringer Ingelheim Investigational Site	Blackpool		United Kingdom
235	1237.6.44009 Boehringer Ingelheim Investigational Site	Blackpool		United Kingdom
236	1237.6.44007 Boehringer Ingelheim Investigational Site	Bristol		United Kingdom
237	1237.6.44010 Boehringer Ingelheim Investigational Site	Chertsey		United Kingdom
238	1237.6.44011 Boehringer Ingelheim Investigational Site	Fleetwood		United Kingdom
239	1237.6.44001 Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
240	1237.6.44008 Boehringer Ingelheim Investigational Site	Midsomer Norton		United Kingdom

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Related Info

Publications

None provided.

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT01431287

Other Study ID Numbers:

1237.6
2009-010669-22

First Posted:

Sep 9, 2011

Last Update Posted:

Jul 16, 2015

Last Verified:

Jun 1, 2015

Additional relevant MeSH terms:

Lung Diseases

Lung Diseases, Obstructive

Pulmonary Disease, Chronic Obstructive

Tiotropium Bromide

Olodaterol

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	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	507	507	508	507
COMPLETED	412	409	410	445	430
NOT COMPLETED	98	98	97	63	77

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 Participants	510	507	506	508	507	2538
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	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 (Count of Participants)
Female	132 25.9%	146 28.8%	134 26.5%	140 27.6%	158 31.2%	710 28%
Male	378 74.1%	361 71.2%	372 73.5%	368 72.4%	349 68.8%	1828 72%

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.
Measure Participants	507	504	500	506	502
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	954	960	954	990	979
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	984	982	978	992	992
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	507	504	500	506	502
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	507	504	500	506	502
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	507	504	500	506	502
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments

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

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5744
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95% -0.018 to 0.033
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0381
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.001 to 0.053
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

12. Secondary Outcome

Title	Trough FEV1 Response on Day 365
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365

Outcome Measure Data

Analysis Population Description
FAS (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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.011 (0.009)	0.022 (0.009)	0.040 (0.009)	0.077 (0.009)	0.093 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.081
	Confidence Interval	(2-Sided) 95% 0.055 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 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.053
	Confidence Interval	(2-Sided) 95% 0.027 to 0.079
	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
	Type of Statistical Test	Superiority or Other
	Comments

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 0.091
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.055
	Confidence Interval	(2-Sided) 95% 0.029 to 0.081
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0052
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95% 0.011 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 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2273
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95% -0.010 to 0.042
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95% 0.045 to 0.097
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0330
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95% 0.002 to 0.055
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4327
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.016 to 0.037
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1764
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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 0.044
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.013
	Estimation Comments	spatial power covariance structure for within-patient errors

13. Secondary Outcome

Title	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1
Description	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.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 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 (day 1). 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.
Measure Participants	507	504	500	506	502
Median (Standard Error) [Litres]	0.341 (0.018)	0.264 (0.018)	0.298 (0.018)	0.411 (0.018)	0.397 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0241
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.056
	Confidence Interval	(2-Sided) 95% 0.007 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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% 0.051 to 0.148
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0049
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.070
	Confidence Interval	(2-Sided) 95% 0.021 to 0.119
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.147
	Confidence Interval	(2-Sided) 95% 0.098 to 0.196
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.113
	Confidence Interval	(2-Sided) 95% 0.064 to 0.162
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5831
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.063 to 0.035
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.133
	Confidence Interval	(2-Sided) 95% 0.084 to 0.182
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0822
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.043
	Confidence Interval	(2-Sided) 95% -0.092 to 0.006
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	-0.077
	Confidence Interval	(2-Sided) 95% -0.126 to -0.028
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1774
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.015 to 0.083
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	Estimation Comments	spatial power covariance structure for within-patient errors

14. Secondary Outcome

Title	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85
Description	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.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 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 (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.
Measure Participants	507	504	500	506	502
Median (Standard Error) [Litres]	0.250 (0.018)	0.306 (0.018)	0.326 (0.018)	0.460 (0.018)	0.469 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.219
	Confidence Interval	(2-Sided) 95% 0.169 to 0.268
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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% 0.094 to 0.193
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.209
	Confidence Interval	(2-Sided) 95% 0.160 to 0.258
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.153
	Confidence Interval	(2-Sided) 95% 0.104 to 0.203
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.134
	Confidence Interval	(2-Sided) 95% 0.084 to 0.183
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6974
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.040 to 0.059
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.163
	Confidence Interval	(2-Sided) 95% 0.114 to 0.213
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0027
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.026 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0269
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.056
	Confidence Interval	(2-Sided) 95% 0.006 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4343
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.030 to 0.069
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	Estimation Comments	spatial power covariance structure for within-patient errors

15. Secondary Outcome

Title	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169
Description	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. 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 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 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
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.
Measure Participants	507	504	500	506	502
Median (Standard Error) [Litres]	0.231 (0.018)	0.247 (0.018)	0.283 (0.018)	0.439 (0.018)	0.429 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.198
	Confidence Interval	(2-Sided) 95% 0.148 to 0.248
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.146
	Confidence Interval	(2-Sided) 95% 0.096 to 0.197
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.208
	Confidence Interval	(2-Sided) 95% 0.158 to 0.258
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.193
	Confidence Interval	(2-Sided) 95% 0.143 to 0.242
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.156
	Confidence Interval	(2-Sided) 95% 0.106 to 0.206
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6980
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.060 to 0.040
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.183
	Confidence Interval	(2-Sided) 95% 0.132 to 0.233
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0442
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95% 0.001 to 0.102
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5514
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.035 to 0.065
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1569
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.036
	Confidence Interval	(2-Sided) 95% -0.014 to 0.086
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	Estimation Comments	spatial power covariance structure for within-patient errors

16. Secondary Outcome

Title	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365
Description	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. 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 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 (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.
Measure Participants	507	504	500	506	502
Median (Standard Error) [Litres]	0.180 (0.019)	0.216 (0.018)	0.198 (0.019)	0.397 (0.018)	0.381 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.202
	Confidence Interval	(2-Sided) 95% 0.150 to 0.253
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.183
	Confidence Interval	(2-Sided) 95% 0.132 to 0.234
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.218
	Confidence Interval	(2-Sided) 95% 0.167 to 0.269
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.181
	Confidence Interval	(2-Sided) 95% 0.130 to 0.232
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.199
	Confidence Interval	(2-Sided) 95% 0.148 to 0.250
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5373
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.016
	Confidence Interval	(2-Sided) 95% -0.067 to 0.035
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.165
	Confidence Interval	(2-Sided) 95% 0.114 to 0.216
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4763
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.019
	Confidence Interval	(2-Sided) 95% -0.033 to 0.070
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1613
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95% -0.015 to 0.088
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4908
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.069 to 0.033
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	Estimation Comments	spatial power covariance structure for within-patient errors

17. Secondary Outcome

Title	Trough FVC Response on Day 15
Description	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.163 (0.018)	0.209 (0.018)	0.222 (0.018)	0.293 (0.018)	0.285 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.122
	Confidence Interval	(2-Sided) 95% 0.072 to 0.173
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0154
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.012 to 0.113
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.130
	Confidence Interval	(2-Sided) 95% 0.080 to 0.181
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0012
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.084
	Confidence Interval	(2-Sided) 95% 0.033 to 0.134
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0061
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95% 0.020 to 0.121
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7518
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.059 to 0.042
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0034
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.025 to 0.126
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0209
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.009 to 0.110
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0708
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.004 to 0.097
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6148
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.038 to 0.064
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	Estimation Comments	spatial power covariance structure for within-patient errors

18. Secondary Outcome

Title	Trough FVC Response on Day 43
Description	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.129 (0.018)	0.206 (0.018)	0.222 (0.018)	0.281 (0.018)	0.293 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.164
	Confidence Interval	(2-Sided) 95% 0.114 to 0.215
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0064
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95% 0.020 to 0.122
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.152
	Confidence Interval	(2-Sided) 95% 0.102 to 0.203
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0035
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95% 0.025 to 0.126
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0233
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.008 to 0.109
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6413
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.039 to 0.063
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.088
	Confidence Interval	(2-Sided) 95% 0.037 to 0.138
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.043 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0030
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.026 to 0.127
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5159
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.034 to 0.068
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	Estimation Comments	spatial power covariance structure for within-patient errors

19. Secondary Outcome

Title	Trough FVC Response on Day 85
Description	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and 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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.063 (0.018)	0.178 (0.018)	0.184 (0.018)	0.246 (0.018)	0.274 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.210
	Confidence Interval	(2-Sided) 95% 0.159 to 0.261
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.089
	Confidence Interval	(2-Sided) 95% 0.038 to 0.141
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.183
	Confidence Interval	(2-Sided) 95% 0.132 to 0.234
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0094
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95% 0.017 to 0.119
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0174
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.062
	Confidence Interval	(2-Sided) 95% 0.011 to 0.113
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2888
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95% -0.023 to 0.079
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.095
	Confidence Interval	(2-Sided) 95% 0.044 to 0.146
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

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% 0.070 to 0.172
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.115
	Confidence Interval	(2-Sided) 95% 0.064 to 0.166
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8241
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95% -0.045 to 0.057
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.026
	Estimation Comments	spatial power covariance structure for within-patient errors

20. Secondary Outcome

Title	Trough FVC Response on Day 170
Description	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day. Trough FVC response was defined as trough FVC minus baseline FVC. 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 23h and at 23h 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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.116 (0.018)	0.163 (0.018)	0.202 (0.018)	0.266 (0.018)	0.274 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.158
	Confidence Interval	(2-Sided) 95% 0.108 to 0.208
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0048
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95% 0.022 to 0.122
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.150
	Confidence Interval	(2-Sided) 95% 0.101 to 0.200
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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% 0.053 to 0.152
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0116
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.014 to 0.113
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7577
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.042 to 0.058
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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% 0.061 to 0.160
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.086
	Confidence Interval	(2-Sided) 95% 0.037 to 0.136
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0621
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.002 to 0.097
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1266
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95% -0.011 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.025
	Estimation Comments	spatial power covariance structure for within-patient errors

21. Secondary Outcome

Title	Trough FVC Response on Day 365
Description	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. 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). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. 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.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365

Outcome Measure Data

Analysis Population Description
FAS (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.
Measure Participants	503	499	498	500	497
Least Squares Mean (Standard Error) [Litres]	0.028 (0.019)	0.096 (0.019)	0.097 (0.019)	0.198 (0.019)	0.184 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.156
	Confidence Interval	(2-Sided) 95% 0.104 to 0.209
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.087
	Confidence Interval	(2-Sided) 95% 0.034 to 0.139
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.170
	Confidence Interval	(2-Sided) 95% 0.118 to 0.223
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.102
	Confidence Interval	(2-Sided) 95% 0.049 to 0.154
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.100
	Confidence Interval	(2-Sided) 95% 0.048 to 0.153
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6093
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.066 to 0.039
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0011
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.035 to 0.140
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.070
	Confidence Interval	(2-Sided) 95% 0.017 to 0.123
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0108
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% 0.016 to 0.121
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9627
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.051 to 0.054
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.027
	Estimation Comments	spatial power covariance structure for within-patient errors

22. Secondary Outcome

Title	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA 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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169

Outcome Measure Data

Analysis Population Description
12 hr PFT set: All patients who have given Informed Consent for the 12-hour PFT testing and had any spirometry measurement after 3-hour and before or at 12-hours post-dose on Days 169 and 170.

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.
Measure Participants	194	185	160	178	167
Least Squares Mean (Standard Error) [Litres]	0.131 (0.015)	0.109 (0.016)	0.127 (0.017)	0.202 (0.016)	0.250 (0.016)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.118
	Confidence Interval	(2-Sided) 95% 0.074 to 0.162
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.123
	Confidence Interval	(2-Sided) 95% 0.077 to 0.169
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.023
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0012
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95% 0.028 to 0.114
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 95% 0.050 to 0.137
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0010
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95% 0.031 to 0.121
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.023
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0384
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95% 0.003 to 0.092
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.023
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.141
	Confidence Interval	(2-Sided) 95% 0.097 to 0.185
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8428
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.004
	Confidence Interval	(2-Sided) 95% -0.049 to 0.040
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.023
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.3048
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.022
	Confidence Interval	(2-Sided) 95% -0.065 to 0.020
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4311
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95% -0.027 to 0.063
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.023
	Estimation Comments

23. Secondary Outcome

Title	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA 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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169

Outcome Measure Data

Analysis Population Description
12-hr PFT set

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.
Measure Participants	194	185	160	178	167
Least Squares Mean (Standard Error) [Litres]	0.108 (0.014)	0.083 (0.015)	0.100 (0.016)	0.159 (0.015)	0.206 (0.015)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95% 0.057 to 0.139
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.106
	Confidence Interval	(2-Sided) 95% 0.063 to 0.149
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0136
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95% 0.010 to 0.091
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95% 0.035 to 0.116
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0065
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95% 0.016 to 0.101
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.022
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0277
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95% 0.005 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.122
	Confidence Interval	(2-Sided) 95% 0.081 to 0.164
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7116
	Comments	Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95% -0.049 to 0.034
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2332
	Comments	Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.024
	Confidence Interval	(2-Sided) 95% -0.065 to 0.016
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.020
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4374
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95% -0.025 to 0.059
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.021
	Estimation Comments

24. Secondary Outcome

Title	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA 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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169

Outcome Measure Data

Analysis Population Description
12-hr PFT set

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.
Measure Participants	194	185	160	178	167
Least Squares Mean (Standard Error) [Litres]	0.227 (0.029)	0.180 (0.030)	0.248 (0.032)	0.356 (0.030)	0.388 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0002
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.161
	Confidence Interval	(2-Sided) 95% 0.077 to 0.244
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0017
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.140
	Confidence Interval	(2-Sided) 95% 0.053 to 0.228
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.045
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0022
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.128
	Confidence Interval	(2-Sided) 95% 0.046 to 0.210
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.042
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.176
	Confidence Interval	(2-Sided) 95% 0.093 to 0.259
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.042
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0141
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95% 0.022 to 0.194
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.044
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4581
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95% -0.053 to 0.118
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.208
	Confidence Interval	(2-Sided) 95% 0.124 to 0.293
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.6335
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.021
	Confidence Interval	(2-Sided) 95% -0.064 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2530
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.047
	Confidence Interval	(2-Sided) 95% -0.129 to 0.034
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1188
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95% -0.017 to 0.153
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

25. Secondary Outcome

Title	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. 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 mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA 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, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169

Outcome Measure Data

Analysis Population Description
12-hr PFT set

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.
Measure Participants	194	185	160	178	167
Least Squares Mean (Standard Error) [Litres]	0.192 (0.028)	0.141 (0.028)	0.203 (0.030)	0.297 (0.029)	0.329 (0.030)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0008
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95% 0.057 to 0.217
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0032
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.126
	Confidence Interval	(2-Sided) 95% 0.042 to 0.209
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.043
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0085
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.105
	Confidence Interval	(2-Sided) 95% 0.027 to 0.183
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.040
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.156
	Confidence Interval	(2-Sided) 95% 0.077 to 0.235
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.040
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0255
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 95% 0.011 to 0.176
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.042
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4393
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95% -0.049 to 0.113
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.188
	Confidence Interval	(2-Sided) 95% 0.108 to 0.269
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7784
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95% -0.069 to 0.092
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1965
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.051
	Confidence Interval	(2-Sided) 95% -0.129 to 0.026
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.039
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1315
	Comments	ANCOVA model with categorical effect of treatment and baseline as covariate.
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95% -0.019 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.041
	Estimation Comments

26. Secondary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 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 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.
Measure Participants	954	960	955	990	979
Least Squares Mean (Standard Error) [points on a scale]	38.832 (0.398)	37.821 (0.397)	37.822 (0.399)	37.304 (0.392)	36.691 (0.394)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	-2.141
	Confidence Interval	(2-Sided) 95% -3.239 to -1.043
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.560
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0435
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.131
	Confidence Interval	(2-Sided) 95% -2.230 to -0.033
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.560
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0063
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.528
	Confidence Interval	(2-Sided) 95% -2.623 to -0.432
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.559
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.3545
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.517
	Confidence Interval	(2-Sided) 95% -1.611 to 0.577
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.558
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.3542
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.518
	Confidence Interval	(2-Sided) 95% -1.614 to 0.578
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.559
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2697
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.613
	Confidence Interval	(2-Sided) 95% -1.702 to 0.476
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.556
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0434
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.130
	Confidence Interval	(2-Sided) 95% -2.227 to -0.033
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.559
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0732
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.010
	Confidence Interval	(2-Sided) 95% -2.114 to 0.095
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.563
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0724
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.011
	Confidence Interval	(2-Sided) 95% -2.114 to 0.092
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.563
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9983
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -1.102 to 1.104
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.563
	Estimation Comments	Spatial power covariance structure for within-patient errors.

27. Secondary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 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 365

Outcome Measure Data

Analysis Population Description
FAS (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.
Measure Participants	954	960	955	990	979
Least Squares Mean (Standard Error) [points on a scale]	38.989 (0.414)	37.609 (0.409)	37.581 (0.411)	37.553 (0.403)	37.138 (0.404)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	-1.852
	Confidence Interval	(2-Sided) 95% -2.985 to -0.718
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.578
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4413
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.444
	Confidence Interval	(2-Sided) 95% -1.573 to 0.686
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.576
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0129
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.437
	Confidence Interval	(2-Sided) 95% -2.569 to -0.304
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.578
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9222
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.056
	Confidence Interval	(2-Sided) 95% -1.182 to 1.070
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.574
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9602
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -1.157 to 1.100
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.576
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4669
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.415
	Confidence Interval	(2-Sided) 95% -1.533 to 0.703
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.570
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4126
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.471
	Confidence Interval	(2-Sided) 95% -1.598 to 0.656
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.575
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0158
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.408
	Confidence Interval	(2-Sided) 95% -2.551 to -0.265
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.583
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0177
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.381
	Confidence Interval	(2-Sided) 95% -2.521 to -0.240
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.582
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9624
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -1.164 to 1.109
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.580
	Estimation Comments	Spatial power covariance structure for within-patient errors.

28. Secondary Outcome

Title	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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 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.
Measure Participants	984	982	978	992	992
Least Squares Mean (Standard Error) [points on a scale]	1.453 (0.096)	1.430 (0.097)	1.408 (0.097)	1.876 (0.096)	2.048 (0.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.595
	Confidence Interval	(2-Sided) 95% 0.329 to 0.862
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.640
	Confidence Interval	(2-Sided) 95% 0.373 to 0.907
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.423
	Confidence Interval	(2-Sided) 95% 0.156 to 0.690
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0011
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.446
	Confidence Interval	(2-Sided) 95% 0.179 to 0.712
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.468
	Confidence Interval	(2-Sided) 95% 0.201 to 0.735
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2045
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.172
	Confidence Interval	(2-Sided) 95% -0.094 to 0.438
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.618
	Confidence Interval	(2-Sided) 95% 0.351 to 0.885
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7432
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.045
	Confidence Interval	(2-Sided) 95% -0.313 to 0.223
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8687
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95% -0.290 to 0.245
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8709
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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% -0.290 to 0.246
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	Estimation Comments	Spatial power covariance structure for within-patient errors.

29. Secondary Outcome

Title	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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 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.
Measure Participants	984	982	978	992	992
Least Squares Mean (Standard Error) [points on a scale]	1.506 (0.097)	1.698 (0.097)	1.702 (0.097)	1.925 (0.096)	2.136 (0.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.630
	Confidence Interval	(2-Sided) 95% 0.362 to 0.898
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0015
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.434
	Confidence Interval	(2-Sided) 95% 0.166 to 0.703
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.419
	Confidence Interval	(2-Sided) 95% 0.151 to 0.687
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0966
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.227
	Confidence Interval	(2-Sided) 95% -0.041 to 0.495
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1029
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.223
	Confidence Interval	(2-Sided) 95% -0.045 to 0.492
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1220
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.211
	Confidence Interval	(2-Sided) 95% -0.056 to 0.478
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.136
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.438
	Confidence Interval	(2-Sided) 95% 0.170 to 0.707
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1542
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.196
	Confidence Interval	(2-Sided) 95% -0.074 to 0.465
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1626
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.192
	Confidence Interval	(2-Sided) 95% -0.077 to 0.461
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.137
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9765
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	djusted mean difference
	Estimated Value	0.004
	Confidence Interval	(2-Sided) 95% -0.265 to 0.274
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.138
	Estimation Comments	Spatial power covariance structure for within-patient errors.

30. Secondary Outcome

Title	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
Description	Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). 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 365

Outcome Measure Data

Analysis Population Description
FAS (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.
Measure Participants	984	982	978	992	992
Least Squares Mean (Standard Error) [points on a scale]	1.411 (0.101)	1.450 (0.100)	1.736 (0.101)	1.782 (0.099)	2.058 (0.099)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

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	0.647
	Confidence Interval	(2-Sided) 95% 0.370 to 0.925
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0226
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.322
	Confidence Interval	(2-Sided) 95% 0.045 to 0.600
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.141
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0089
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.371
	Confidence Interval	(2-Sided) 95% 0.093 to 0.649
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0186
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.332
	Confidence Interval	(2-Sided) 95% 0.056 to 0.609
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.141
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7441
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.046
	Confidence Interval	(2-Sided) 95% -0.231 to 0.324
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0492
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.276
	Confidence Interval	(2-Sided) 95% 0.001 to 0.551
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.140
	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
	Type of Statistical Test	Superiority or Other
	Comments

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	0.608
	Confidence Interval	(2-Sided) 95% 0.332 to 0.884
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.141
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0230
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.325
	Confidence Interval	(2-Sided) 95% 0.045 to 0.605
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.143
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7855
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95% -0.240 to 0.317
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	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
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0442
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.

Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.286
	Confidence Interval	(2-Sided) 95% 0.007 to 0.564
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	Estimation Comments	Spatial power covariance structure for within-patient errors.

Adverse Events

	Olodaterol (5 μg)		Tiotropium (2.5 μg)		Tiotropium (5 μg)		Tio+Olo FDC (2.5/5 μg)		Tio+Olo FDC (5/5 μg)
Time Frame	All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Adverse Event Reporting Description

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.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Olodaterol (5 μg)		Tiotropium (2.5 μg)		Tiotropium (5 μg)		Tio+Olo FDC (2.5/5 μg)		Tio+Olo FDC (5/5 μg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/510 (20.8%)		90/507 (17.8%)		93/506 (18.4%)		87/508 (17.1%)		82/507 (16.2%)
Blood and lymphatic system disorders
Anaemia	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Haemorrhagic anaemia	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Iron deficiency anaemia	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Cardiac disorders
Acute coronary syndrome	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Acute myocardial infarction	2/510 (0.4%)		1/507 (0.2%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Angina pectoris	3/510 (0.6%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Angina unstable	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Aortic valve stenosis	0/510 (0%)		2/507 (0.4%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Atrial fibrillation	1/510 (0.2%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Atrial flutter	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Cardiac arrest	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		2/508 (0.4%)		0/507 (0%)
Cardiac disorder	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Cardiac failure	2/510 (0.4%)		0/507 (0%)		2/506 (0.4%)		1/508 (0.2%)		0/507 (0%)
Cardiac failure acute	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cardiac failure congestive	1/510 (0.2%)		2/507 (0.4%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cardio-respiratory arrest	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Coronary artery disease	2/510 (0.4%)		1/507 (0.2%)		3/506 (0.6%)		1/508 (0.2%)		2/507 (0.4%)
Extrasystoles	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Ischaemic cardiomyopathy	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Left ventricular dysfunction	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Myocardial infarction	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		2/508 (0.4%)		1/507 (0.2%)
Myocardial ischaemia	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Palpitations	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Supraventricular tachycardia	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Tachyarrhythmia	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Ventricular fibrillation	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Ventricular tachycardia	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Congenital, familial and genetic disorders
Malformation biliary	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Ear and labyrinth disorders
Vertigo	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Eye disorders
Age-related macular degeneration	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Cataract	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Lacrimation increased	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Macular degeneration	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Retinal tear	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Vision blurred	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Gastrointestinal disorders
Abdominal pain	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Abdominal pain upper	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Colitis	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Colitis ischaemic	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Colitis ulcerative	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Crohn's disease	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Diarrhoea	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Diverticulum intestinal	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Duodenal ulcer haemorrhage	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Duodenal ulcer perforation	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Dysphagia	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Enteritis	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Gastritis	0/510 (0%)		2/507 (0.4%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Gastrointestinal haemorrhage	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Gastrooesophageal reflux disease	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Ileus	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Inguinal hernia	3/510 (0.6%)		1/507 (0.2%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Inguinal hernia strangulated	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Melaena	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Mesenteric artery stenosis	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Oesophageal achalasia	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Oesophageal stenosis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Oral pain	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Pancreatitis acute	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Proctalgia	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Small intestinal obstruction	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Upper gastrointestinal haemorrhage	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
General disorders
Chest discomfort	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Chest pain	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		2/508 (0.4%)		0/507 (0%)
Death	1/510 (0.2%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Device dislocation	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Drowning	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Generalised oedema	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Medical device complication	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Multi-organ failure	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Non-cardiac chest pain	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		2/507 (0.4%)
Oedema peripheral	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		2/508 (0.4%)		0/507 (0%)
Pyrexia	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Sudden death	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Hepatobiliary disorders
Bile duct stone	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Biliary colic	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cholecystitis	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Cholecystitis acute	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		2/508 (0.4%)		0/507 (0%)
Cholelithiasis	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Infections and infestations
Abscess	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Anal abscess	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Appendicitis perforated	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Biliary sepsis	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Bronchitis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		2/507 (0.4%)
Bronchopneumonia	2/510 (0.4%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cellulitis	2/510 (0.4%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Cellulitis pharyngeal	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Dermatitis infected	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Diverticulitis	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Escherichia bacteraemia	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Gastroenteritis	0/510 (0%)		1/507 (0.2%)		2/506 (0.4%)		0/508 (0%)		0/507 (0%)
Gastroenteritis viral	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Graft infection	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
H1N1 influenza	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Hepatitis B	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Infection	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Infective exacerbation of chronic obstructive airways disease	2/510 (0.4%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Influenza	2/510 (0.4%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Lobar pneumonia	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Lower respiratory tract infection	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Lung infection	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Ophthalmic herpes zoster	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pelvic abscess	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pneumococcal sepsis	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pneumonia	6/510 (1.2%)		6/507 (1.2%)		2/506 (0.4%)		9/508 (1.8%)		9/507 (1.8%)
Post procedural infection	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Postoperative abscess	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pyelonephritis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Respiratory tract infection	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Sepsis	1/510 (0.2%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Septic shock	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Sinusitis	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Superinfection	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Urinary tract infection	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Urosepsis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Injury, poisoning and procedural complications
Abdominal injury	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Acetabulum fracture	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Avulsion fracture	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Clavicle fracture	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Contusion	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Fall	3/510 (0.6%)		1/507 (0.2%)		0/506 (0%)		2/508 (0.4%)		1/507 (0.2%)
Femoral neck fracture	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Femur fracture	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Head injury	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Hip fracture	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Humerus fracture	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Injury	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Joint dislocation	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Liver contusion	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Lumbar vertebral fracture	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Meniscus injury	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Patella fracture	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Rib fracture	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		2/507 (0.4%)
Skull fractured base	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Spinal compression fracture	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Stab wound	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Subdural haematoma	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Tendon rupture	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Thoracic vertebral fracture	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Traumatic haematoma	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Vascular pseudoaneurysm	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Investigations
Blood glucose increased	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Blood pressure decreased	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Troponin T increased	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Metabolism and nutrition disorders
Dehydration	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		2/507 (0.4%)
Diabetes mellitus	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Diabetic ketoacidosis	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Gout	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Hypokalaemia	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Back pain	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Bone deformity	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Flank pain	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Foot deformity	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Intervertebral disc degeneration	1/510 (0.2%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Intervertebral disc protrusion	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Lumbar spinal stenosis	0/510 (0%)		0/507 (0%)		0/506 (0%)		2/508 (0.4%)		0/507 (0%)
Monarthritis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Musculoskeletal pain	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Osteoarthritis	2/510 (0.4%)		2/507 (0.4%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Periarthritis	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Spinal column stenosis	0/510 (0%)		3/507 (0.6%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Spinal osteoarthritis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Spondylolisthesis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Synovial cyst	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Basal cell carcinoma	1/510 (0.2%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Bladder cancer	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Bladder neoplasm	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Bronchial carcinoma	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Colon adenoma	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Colon cancer	2/510 (0.4%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Endometrial cancer	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Gastric cancer	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Hepatic cancer	0/510 (0%)		2/507 (0.4%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Lung adenocarcinoma	1/510 (0.2%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Lung adenocarcinoma metastatic	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Lung cancer metastatic	2/510 (0.4%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Lung neoplasm	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Lung neoplasm malignant	1/510 (0.2%)		1/507 (0.2%)		2/506 (0.4%)		2/508 (0.4%)		0/507 (0%)
Metastases to adrenals	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Metastases to central nervous system	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Metastases to liver	2/510 (0.4%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Neoplasm prostate	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Neuroendocrine carcinoma	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Non-small cell lung cancer	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Oesophageal carcinoma	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Oesophageal squamous cell carcinoma	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Oropharyngeal cancer	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		1/507 (0.2%)
Pancreatic carcinoma	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Penile cancer	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Prostate cancer	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		2/508 (0.4%)		1/507 (0.2%)
Prostate cancer metastatic	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Rectal cancer	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Renal cancer	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Renal cancer metastatic	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Small cell lung cancer	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Squamous cell carcinoma of lung	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Squamous cell carcinoma of skin	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Squamous cell carcinoma of the tongue	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Sweat gland tumour	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Transitional cell carcinoma	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Nervous system disorders
Acute polyneuropathy	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Carotid artery aneurysm	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Carotid artery stenosis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Cerebellar haemorrhage	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cerebral haemorrhage	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Cerebral infarction	0/510 (0%)		0/507 (0%)		0/506 (0%)		2/508 (0.4%)		0/507 (0%)
Cerebrovascular accident	0/510 (0%)		1/507 (0.2%)		2/506 (0.4%)		0/508 (0%)		2/507 (0.4%)
Cerebrovascular disorder	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Convulsion	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Dizziness	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Epilepsy	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Haemorrhage intracranial	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Headache	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Hypoxic-ischaemic encephalopathy	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Nervous system disorder	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Neuromyopathy	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Presyncope	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Spondylitic myelopathy	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Subarachnoid haemorrhage	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Syncope	1/510 (0.2%)		1/507 (0.2%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Thrombotic cerebral infarction	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Transient ischaemic attack	2/510 (0.4%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Tremor	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Psychiatric disorders
Acute stress disorder	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Aggression	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Bipolar I disorder	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Confusional state	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Conversion disorder	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Delirium	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Depression	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Major depression	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Renal and urinary disorders
Dysuria	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Haematuria	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		1/508 (0.2%)		0/507 (0%)
Nephritis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Renal colic	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Renal failure	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Renal failure acute	0/510 (0%)		1/507 (0.2%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Renal vasculitis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/510 (0%)		1/507 (0.2%)		4/506 (0.8%)		1/508 (0.2%)		1/507 (0.2%)
Vaginal prolapse	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/510 (0.4%)		2/507 (0.4%)		1/506 (0.2%)		2/508 (0.4%)		0/507 (0%)
Analgesic asthma syndrome	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Atelectasis	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Bronchiectasis	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Bullous lung disease	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Chronic obstructive pulmonary disease	41/510 (8%)		37/507 (7.3%)		33/506 (6.5%)		30/508 (5.9%)		33/507 (6.5%)
Dysphonia	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Dyspnoea	0/510 (0%)		2/507 (0.4%)		2/506 (0.4%)		1/508 (0.2%)		2/507 (0.4%)
Emphysema	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Epistaxis	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Haemoptysis	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Hydrothorax	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Hypercapnia	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Hypoxia	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		1/507 (0.2%)
Interstitial lung disease	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Nasal polyps	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Nasal turbinate hypertrophy	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Paranasal sinus discomfort	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pleural effusion	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Pneumonia aspiration	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Pneumothorax	0/510 (0%)		0/507 (0%)		3/506 (0.6%)		0/508 (0%)		1/507 (0.2%)
Pneumothorax spontaneous	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pulmonary embolism	2/510 (0.4%)		2/507 (0.4%)		0/506 (0%)		3/508 (0.6%)		0/507 (0%)
Pulmonary granuloma	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Pulmonary hypertension	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Pulmonary infarction	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Pulmonary mass	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Pulmonary oedema	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Respiratory failure	0/510 (0%)		1/507 (0.2%)		3/506 (0.6%)		0/508 (0%)		3/507 (0.6%)
Rhonchi	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Vocal cord polyp	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Skin and subcutaneous tissue disorders
Eczema	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Vascular disorders
Aneurysm	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Aortic aneurysm	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Aortic aneurysm rupture	0/510 (0%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		1/507 (0.2%)
Arteritis	0/510 (0%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Deep vein thrombosis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Haemorrhage	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Hypertension	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Hypertensive crisis	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Hypotension	1/510 (0.2%)		1/507 (0.2%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Intermittent claudication	1/510 (0.2%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Leriche syndrome	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Peripheral arterial occlusive disease	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Peripheral artery aneurysm	0/510 (0%)		0/507 (0%)		1/506 (0.2%)		0/508 (0%)		0/507 (0%)
Peripheral artery stenosis	0/510 (0%)		0/507 (0%)		0/506 (0%)		1/508 (0.2%)		0/507 (0%)
Shock	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Thrombophlebitis	1/510 (0.2%)		0/507 (0%)		0/506 (0%)		0/508 (0%)		0/507 (0%)
Other (Not Including Serious) Adverse Events
	Olodaterol (5 μg)		Tiotropium (2.5 μg)		Tiotropium (5 μg)		Tio+Olo FDC (2.5/5 μg)		Tio+Olo FDC (5/5 μg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	246/510 (48.2%)		228/507 (45%)		216/506 (42.7%)		223/508 (43.9%)		214/507 (42.2%)
Infections and infestations
Nasopharyngitis	66/510 (12.9%)		59/507 (11.6%)		54/506 (10.7%)		70/508 (13.8%)		61/507 (12%)
Upper respiratory tract infection	32/510 (6.3%)		31/507 (6.1%)		27/506 (5.3%)		29/508 (5.7%)		29/507 (5.7%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	147/510 (28.8%)		146/507 (28.8%)		132/506 (26.1%)		118/508 (23.2%)		129/507 (25.4%)
Cough	17/510 (3.3%)		27/507 (5.3%)		25/506 (4.9%)		29/508 (5.7%)		24/507 (4.7%)
Dyspnoea	20/510 (3.9%)		22/507 (4.3%)		27/506 (5.3%)		21/508 (4.1%)		20/507 (3.9%)
Vascular disorders
Hypertension	26/510 (5.1%)		10/507 (2%)		10/506 (2%)		19/508 (3.7%)		12/507 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Name/Title	Boehringer Ingelheim Call Center
Organization	Boehringer Ingelheim
Phone	1-800-243-0127
Email	clintriage.rdg@boehringer-ingelheim.com

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT01431287

Other Study ID Numbers:

1237.6
2009-010669-22

First Posted:

Sep 9, 2011

Last Update Posted:

Jul 16, 2015

Last Verified:

Jun 1, 2015