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: NCT01431274
• Collaborator: (none)
• Enrollment: 2,624
• Locations: 239
• Arms: 5
• Duration (Months): 24
• Patients Per Site: 11
• Patients Per Site Per Month: 0.5

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 Chronic Obstructive Pulmonary Disease (COPD).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 2624 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 1]
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

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

1. Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [Day 169]

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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. Trough FEV1 Response on Day 85 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85.]

   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.

8. Trough FEV1 Response on Day 169 [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169]

   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.

9. 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.

10. FVC (Forced Vital Capacity) 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.

11. FVC (Forced Vital Capacity) 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.

12. FVC (Forced Vital Capacity) 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.

13. FVC (Forced Vital Capacity) 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.

14. 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.

15. 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.

16. 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.

17. Trough FVC 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 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.

18. 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.

19. FEV1 AUC(0-12h) Response in the Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

20. FEV1 AUC(0-24h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

21. FVC AUC(0-12h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

22. FVC AUC(0-24h) Response in Sub-set of Patients With 24-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

23. Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

24. Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [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.

25. Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [Day 43]

    Mahler Transitional Dyspnoea Index (TDI) focal score on Day 43 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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.

26. Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [Day 85]

    Mahler Transitional Dyspnoea Index (TDI) focal score on Day 85 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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.

27. Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) [Day 365]

    Mahler Transitional Dyspnoea Index (TDI) focal score on Day 365 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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: No

Inclusion criteria:

1. Diagnosis of chronic obstructive pulmonary disease.

2. Relatively stable airway obstruction with post FEV1< 80% predicted normal and post FEV1/FVC <70%.

3. Male or female patients, 40 years of age or older.

4. Smoking history of more than 10 pack years.

Exclusion criteria:

1. Significant disease other than COPD

2. Clinically relevant abnormal lab values.

3. History of asthma.

4. Diagnosis of thyrotoxicosis

5. Diagnosis of paroxysmal tachycardia

6. History of myocardial infarction within 1 year of screening visit

7. Unstable or life-threatening cardiac arrhythmia.

8. Hospitalization for heart failure within the past year.

9. Known active tuberculosis.

10. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years

11. History of life-threatening pulmonary obstruction.

12. History of cystic fibrosis.

13. Clinically evident bronchiectasis.

14. History of significant alcohol or drug abuse.

15. Thoracotomy with pulmonary resection

16. Oral ß-adrenergics.

17. Oral corticosteroid medication at unstable doses

18. Regular use of daytime oxygen therapy for more than one hour per day

19. Pulmonary rehabilitation program in the six weeks prior to the screening visit

20. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit

21. Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA

22. Pregnant or nursing women.

23. Women of childbearing potential not using a highly effective method of birth control

24. Patients who are unable to comply with pulmonary medication restrictions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1237.5.01038 Boehringer Ingelheim Investigational Site	Jasper	Alabama	United States
2	1237.5.01036 Boehringer Ingelheim Investigational Site	Mobile	Alabama	United States
3	1237.5.01015 Boehringer Ingelheim Investigational Site	Boulder	Colorado	United States
4	1237.5.01024 Boehringer Ingelheim Investigational Site	Wheat Ridge	Colorado	United States
5	1237.5.01034 Boehringer Ingelheim Investigational Site	Stamford	Connecticut	United States
6	1237.5.01003 Boehringer Ingelheim Investigational Site	Clearwater	Florida	United States
7	1237.5.01010 Boehringer Ingelheim Investigational Site	Clearwater	Florida	United States
8	1237.5.01027 Boehringer Ingelheim Investigational Site	Panama City	Florida	United States
9	1237.5.01031 Boehringer Ingelheim Investigational Site	O'Fallon	Illinois	United States
10	1237.5.01035 Boehringer Ingelheim Investigational Site	Opelousas	Louisiana	United States
11	1237.5.01004 Boehringer Ingelheim Investigational Site	Shreveport	Louisiana	United States
12	1237.5.01017 Boehringer Ingelheim Investigational Site	Biddeford	Maine	United States
13	1237.5.01028 Boehringer Ingelheim Investigational Site	Columbia	Maryland	United States
14	1237.5.01013 Boehringer Ingelheim Investigational Site	Livonia	Michigan	United States
15	1237.5.01019 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
16	1237.5.01025 Boehringer Ingelheim Investigational Site	Larchmont	New York	United States
17	1237.5.01008 Boehringer Ingelheim Investigational Site	Rochester	New York	United States
18	1237.5.01023 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina	United States
19	1237.5.01016 Boehringer Ingelheim Investigational Site	Tabor City	North Carolina	United States
20	1237.5.01006 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
21	1237.5.01040 Boehringer Ingelheim Investigational Site	Columbus	Ohio	United States
22	1237.5.01039 Boehringer Ingelheim Investigational Site	Dayton	Ohio	United States
23	1237.5.01037 Boehringer Ingelheim Investigational Site	Toledo	Ohio	United States
24	1237.5.01009 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
25	1237.5.01032 Boehringer Ingelheim Investigational Site	Charleston	Pennsylvania	United States
26	1237.5.01005 Boehringer Ingelheim Investigational Site	Johnston	Rhode Island	United States
27	1237.5.01021 Boehringer Ingelheim Investigational Site	Easley	South Carolina	United States
28	1237.5.01012 Boehringer Ingelheim Investigational Site	Gaffney	South Carolina	United States
29	1237.5.01014 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina	United States
30	1237.5.01029 Boehringer Ingelheim Investigational Site	Ft. Worth	Texas	United States
31	1237.5.01002 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
32	1237.5.01026 Boehringer Ingelheim Investigational Site	Lynchburg	Virginia	United States
33	1237.5.01007 Boehringer Ingelheim Investigational Site	Spokane	Washington	United States
34	1237.5.01033 Boehringer Ingelheim Investigational Site	Tacoma	Washington	United States
35	1237.5.01001 Boehringer Ingelheim Investigational Site	Morgantown	West Virginia	United States
36	1237.5.54010 Boehringer Ingelheim Investigational Site	Buenos Aires		Argentina
37	1237.5.54013 Boehringer Ingelheim Investigational Site	Caba		Argentina
38	1237.5.54016 Boehringer Ingelheim Investigational Site	Caba		Argentina
39	1237.5.54003 Boehringer Ingelheim Investigational Site	Capital Federal		Argentina
40	1237.5.54002 Boehringer Ingelheim Investigational Site	Cuidad Autonoma de Buenos Airess A		Argentina
41	1237.5.54006 Boehringer Ingelheim Investigational Site	Mar del Plata		Argentina
42	1237.5.54007 Boehringer Ingelheim Investigational Site	Mar del Plata		Argentina
43	1237.5.54009 Boehringer Ingelheim Investigational Site	Mendoza		Argentina
44	1237.5.54012 Boehringer Ingelheim Investigational Site	Monte Grande		Argentina
45	1237.5.54008 Boehringer Ingelheim Investigational Site	Quilmes		Argentina
46	1237.5.54005 Boehringer Ingelheim Investigational Site	Rosario		Argentina
47	1237.5.54011 Boehringer Ingelheim Investigational Site	San Miguel de Tucuman		Argentina
48	1237.5.54004 Boehringer Ingelheim Investigational Site	San Miguel de Tucuma		Argentina
49	1237.5.61001 Boehringer Ingelheim Investigational Site	Toorak Gardens	South Australia	Australia
50	1237.5.61002 Boehringer Ingelheim Investigational Site	Woodville	South Australia	Australia
51	1237.5.61004 Boehringer Ingelheim Investigational Site	Frankston	Victoria	Australia
52	1237.5.35905 Boehringer Ingelheim Investigational Site	Plovdiv		Bulgaria
53	1237.5.35901 Boehringer Ingelheim Investigational Site	Rousse		Bulgaria
54	1237.5.35906 Boehringer Ingelheim Investigational Site	Shumen		Bulgaria
55	1237.5.35902 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
56	1237.5.35904 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
57	1237.5.35903 Boehringer Ingelheim Investigational Site	Troyan		Bulgaria
58	1237.5.35908 Boehringer Ingelheim Investigational Site	Veliko Tarnovo		Bulgaria
59	1237.5.02002 Boehringer Ingelheim Investigational Site	Calgary	Alberta	Canada
60	1237.5.02001 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia	Canada
61	1237.5.02004 Boehringer Ingelheim Investigational Site	Winnipeg	Manitoba	Canada
62	1237.5.02005 Boehringer Ingelheim Investigational Site	Burlington	Ontario	Canada
63	1237.5.02007 Boehringer Ingelheim Investigational Site	Grimsby	Ontario	Canada
64	1237.5.02011 Boehringer Ingelheim Investigational Site	Ottawa	Ontario	Canada
65	1237.5.02008 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec	Canada
66	1237.5.02009 Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan	Canada
67	1237.5.02003 Boehringer Ingelheim Investigational Site	Quebec		Canada
68	1237.5.02006 Boehringer Ingelheim Investigational Site	Quebec		Canada
69	1237.5.86003 Boehringer Ingelheim Investigational Site	Beijing		China
70	1237.5.86004 Boehringer Ingelheim Investigational Site	Beijing		China
71	1237.5.86011 Boehringer Ingelheim Investigational Site	Changsha		China
72	1237.5.86012 Boehringer Ingelheim Investigational Site	Changsha		China
73	1237.5.86014 Boehringer Ingelheim Investigational Site	Foshan		China
74	1237.5.86001 Boehringer Ingelheim Investigational Site	Guangzhou		China
75	1237.5.86015 Boehringer Ingelheim Investigational Site	Nan Ning		China
76	1237.5.86002 Boehringer Ingelheim Investigational Site	Shanghai		China
77	1237.5.86005 Boehringer Ingelheim Investigational Site	Shanghai		China
78	1237.5.86006 Boehringer Ingelheim Investigational Site	Shanghai		China
79	1237.5.86007 Boehringer Ingelheim Investigational Site	Shanghai		China
80	1237.5.86009 Boehringer Ingelheim Investigational Site	Shenyang		China
81	1237.5.86016 Boehringer Ingelheim Investigational Site	Wuhan		China
82	1237.5.86010 Boehringer Ingelheim Investigational Site	Xi'An		China
83	1237.5.86008 Boehringer Ingelheim Investigational Site	Yangzhou		China
84	1237.5.86017 Boehringer Ingelheim Investigational Site	Yinchuan		China
85	1237.5.42004 Boehringer Ingelheim Investigational Site	Beroun		Czech Republic
86	1237.5.42002 Boehringer Ingelheim Investigational Site	Cvikov		Czech Republic
87	1237.5.42001 Boehringer Ingelheim Investigational Site	Praha 6		Czech Republic
88	1237.5.42005 Boehringer Ingelheim Investigational Site	Rokycany		Czech Republic
89	1237.5.42003 Boehringer Ingelheim Investigational Site	Znojmo		Czech Republic
90	1237.5.45002 Boehringer Ingelheim Investigational Site	Aalborg		Denmark
91	1237.5.45009 Boehringer Ingelheim Investigational Site	Hvidovre		Denmark
92	1237.5.45007 Boehringer Ingelheim Investigational Site	Kolding		Denmark
93	1237.5.45001 Boehringer Ingelheim Investigational Site	København NV		Denmark
94	1237.5.45011 Boehringer Ingelheim Investigational Site	Næstved		Denmark
95	1237.5.45006 Boehringer Ingelheim Investigational Site	Odense C		Denmark
96	1237.5.45008 Boehringer Ingelheim Investigational Site	Roskilde		Denmark
97	1237.5.45003 Boehringer Ingelheim Investigational Site	Silkeborg		Denmark
98	1237.5.45005 Boehringer Ingelheim Investigational Site	Sønderborg		Denmark
99	1237.5.45004 Boehringer Ingelheim Investigational Site	Vaerløse		Denmark
100	1237.5.37002 Boehringer Ingelheim Investigational Site	Tallin		Estonia
101	1237.5.37001 Boehringer Ingelheim Investigational Site	Tartu		Estonia
102	1237.5.35801 Boehringer Ingelheim Investigational Site	Helsinki		Finland
103	1237.5.35804 Boehringer Ingelheim Investigational Site	Pori		Finland
104	1237.5.35802 Boehringer Ingelheim Investigational Site	Turku		Finland
105	1237.5.33004 Boehringer Ingelheim Investigational Site	Bethune Cedex		France
106	1237.5.33007 Boehringer Ingelheim Investigational Site	Montpellier cedex 5		France
107	1237.5.33005 Boehringer Ingelheim Investigational Site	Nantes		France
108	1237.5.33006 Boehringer Ingelheim Investigational Site	Nîmes cedex 9		France
109	1237.5.33008 Boehringer Ingelheim Investigational Site	Perpignan		France
110	1237.5.33001 Boehringer Ingelheim Investigational Site	Saint Pierre Cedex		France
111	1237.5.33002 Boehringer Ingelheim Investigational Site	Strasbourg		France
112	1237.5.49006 Boehringer Ingelheim Investigational Site	Bamberg		Germany
113	1237.5.49002 Boehringer Ingelheim Investigational Site	Berlin		Germany
114	1237.5.49003 Boehringer Ingelheim Investigational Site	Berlin		Germany
115	1237.5.49013 Boehringer Ingelheim Investigational Site	Berlin		Germany
116	1237.5.49011 Boehringer Ingelheim Investigational Site	Erfurt		Germany
117	1237.5.49005 Boehringer Ingelheim Investigational Site	Hamburg		Germany
118	1237.5.49010 Boehringer Ingelheim Investigational Site	Hamburg		Germany
119	1237.5.49009 Boehringer Ingelheim Investigational Site	Koblenz		Germany
120	1237.5.49014 Boehringer Ingelheim Investigational Site	Neu-Isenburg		Germany
121	1237.5.49012 Boehringer Ingelheim Investigational Site	Oschersleben		Germany
122	1237.5.49001 Boehringer Ingelheim Investigational Site	Rüdersdorf		Germany
123	1237.5.49004 Boehringer Ingelheim Investigational Site	Weinheim		Germany
124	1237.5.49008 Boehringer Ingelheim Investigational Site	Wiesloch		Germany
125	1237.5.50201 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
126	1237.5.50202 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
127	1237.5.50203 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
128	1237.5.50204 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
129	1237.5.50205 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
130	1237.5.50206 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
131	1237.5.50207 Boehringer Ingelheim Investigational Site	Guatemala		Guatemala
132	1237.5.36005 Boehringer Ingelheim Investigational Site	Debrecen		Hungary
133	1237.5.36001 Boehringer Ingelheim Investigational Site	Deszk		Hungary
134	1237.5.36006 Boehringer Ingelheim Investigational Site	Kapuvar		Hungary
135	1237.5.36003 Boehringer Ingelheim Investigational Site	Szombathely		Hungary
136	1237.5.36002 Boehringer Ingelheim Investigational Site	Törökbalint		Hungary
137	1237.5.91010 Boehringer Ingelheim Investigational Site	Ahmedabad		India
138	1237.5.91002 Boehringer Ingelheim Investigational Site	Bangalore		India
139	1237.5.91007 Boehringer Ingelheim Investigational Site	Bangalore		India
140	1237.5.91004 Boehringer Ingelheim Investigational Site	Coimbatore		India
141	1237.5.91011 Boehringer Ingelheim Investigational Site	Hyderabad		India
142	1237.5.91001 Boehringer Ingelheim Investigational Site	Jaipur		India
143	1237.5.91008 Boehringer Ingelheim Investigational Site	Jaipur		India
144	1237.5.91009 Boehringer Ingelheim Investigational Site	Mysore		India
145	1237.5.91006 Boehringer Ingelheim Investigational Site	Pune		India
146	1237.5.39008 Boehringer Ingelheim Investigational Site	Cagliari		Italy
147	1237.5.39002 Boehringer Ingelheim Investigational Site	Genova		Italy
148	1237.5.39006 Boehringer Ingelheim Investigational Site	Montescano (PV)		Italy
149	1237.5.39009 Boehringer Ingelheim Investigational Site	Monza		Italy
150	1237.5.39004 Boehringer Ingelheim Investigational Site	Parma		Italy
151	1237.5.39001 Boehringer Ingelheim Investigational Site	Pisa		Italy
152	1237.5.81003 Boehringer Ingelheim Investigational Site	Aoba-ku, Sendai, Miyagi		Japan
153	1237.5.81001 Boehringer Ingelheim Investigational Site	Asahikawa, Hokkaido		Japan
154	1237.5.81006 Boehringer Ingelheim Investigational Site	Bunkyo-ku, Tokyo		Japan
155	1237.5.81044 Boehringer Ingelheim Investigational Site	Chuo-ku, Kumamoto, Kumamoto		Japan
156	1237.5.81035 Boehringer Ingelheim Investigational Site	Gifu, Gifu		Japan
157	1237.5.81017 Boehringer Ingelheim Investigational Site	Hakata-ku, Fukuoka, Fukuoka		Japan
158	1237.5.81031 Boehringer Ingelheim Investigational Site	Hamamatsushi, Shizuoka		Japan
159	1237.5.81014 Boehringer Ingelheim Investigational Site	Himeji, Hyogo		Japan
160	1237.5.81037 Boehringer Ingelheim Investigational Site	Ikoma, Nara		Japan
161	1237.5.81024 Boehringer Ingelheim Investigational Site	Inashiki-gun, Ibaraki		Japan
162	1237.5.81008 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo		Japan
163	1237.5.81016 Boehringer Ingelheim Investigational Site	Jonan-ku, Fukuoka, Fukuoka		Japan
164	1237.5.81020 Boehringer Ingelheim Investigational Site	Kagoshima, Kagoshima,		Japan
165	1237.5.81021 Boehringer Ingelheim Investigational Site	Kagoshima, Kagoshima		Japan
166	1237.5.81005 Boehringer Ingelheim Investigational Site	Kamogawa, Chiba		Japan
167	1237.5.81011 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka		Japan
168	1237.5.81018 Boehringer Ingelheim Investigational Site	Kitakyusyu,Fukuoka		Japan
169	1237.5.81042 Boehringer Ingelheim Investigational Site	Koga, Fukuoka		Japan
170	1237.5.81032 Boehringer Ingelheim Investigational Site	Komaki, Aichi		Japan
171	1237.5.81033 Boehringer Ingelheim Investigational Site	Komaki, Aichi		Japan
172	1237.5.81019 Boehringer Ingelheim Investigational Site	Koshi, Kumamoto		Japan
173	1237.5.81027 Boehringer Ingelheim Investigational Site	koto-ku, Tokyo		Japan
174	1237.5.81025 Boehringer Ingelheim Investigational Site	Kuki, Saitama		Japan
175	1237.5.81038 Boehringer Ingelheim Investigational Site	Kure, Hiroshima		Japan
176	1237.5.81015 Boehringer Ingelheim Investigational Site	Kurume, Fukuoka		Japan
177	1237.5.81029 Boehringer Ingelheim Investigational Site	Matsumoto, Nagano		Japan
178	1237.5.81030 Boehringer Ingelheim Investigational Site	Matsumoto, Nagano		Japan
179	1237.5.81010 Boehringer Ingelheim Investigational Site	Matsusaka, Mie		Japan
180	1237.5.81041 Boehringer Ingelheim Investigational Site	Minami-ku. Fukuoka, Fukuoka		Japan
181	1237.5.81002 Boehringer Ingelheim Investigational Site	Morioka, Iwate		Japan
182	1237.5.81034 Boehringer Ingelheim Investigational Site	Nagoya, Aichi		Japan
183	1237.5.81036 Boehringer Ingelheim Investigational Site	Nagoya, Aichi		Japan
184	1237.5.81004 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki		Japan
185	1237.5.81022 Boehringer Ingelheim Investigational Site	Okinawa, Urasoe		Japan
186	1237.5.81023 Boehringer Ingelheim Investigational Site	Okinawa, Urasoe		Japan
187	1237.5.81012 Boehringer Ingelheim Investigational Site	Sayama, Osaka		Japan
188	1237.5.81045 Boehringer Ingelheim Investigational Site	Sendai, Miyagi		Japan
189	1237.5.81009 Boehringer Ingelheim Investigational Site	Seto, Aichi		Japan
190	1237.5.81026 Boehringer Ingelheim Investigational Site	Shinagawa, Tokyo		Japan
191	1237.5.81007 Boehringer Ingelheim Investigational Site	Shinjyuku-ku, Tokyo		Japan
192	1237.5.81039 Boehringer Ingelheim Investigational Site	Takamatsu, Kagawa		Japan
193	1237.5.81040 Boehringer Ingelheim Investigational Site	Takamatsu, Kagawa		Japan
194	1237.5.81013 Boehringer Ingelheim Investigational Site	Wakayama, Wakayama		Japan
195	1237.5.81043 Boehringer Ingelheim Investigational Site	Yanagawa-shi, Fukuoka,		Japan
196	1237.5.81028 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa		Japan
197	1237.5.82004 Boehringer Ingelheim Investigational Site	Bucheon		Korea, Republic of
198	1237.5.82008 Boehringer Ingelheim Investigational Site	Daegu		Korea, Republic of
199	1237.5.82001 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
200	1237.5.82002 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
201	1237.5.82003 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
202	1237.5.82007 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
203	1237.5.82005 Boehringer Ingelheim Investigational Site	Suwon		Korea, Republic of
204	1237.5.82006 Boehringer Ingelheim Investigational Site	Wonju		Korea, Republic of
205	1237.5.52002 Boehringer Ingelheim Investigational Site	Hermosillo		Mexico
206	1237.5.52003 Boehringer Ingelheim Investigational Site	Mexico		Mexico
207	1237.5.52007 Boehringer Ingelheim Investigational Site	Monterrey		Mexico
208	1237.5.52001 Boehringer Ingelheim Investigational Site	Tijuana		Mexico
209	1237.5.31004 Boehringer Ingelheim Investigational Site	Almelo		Netherlands
210	1237.5.31006 Boehringer Ingelheim Investigational Site	Breda		Netherlands
211	1237.5.31001 Boehringer Ingelheim Investigational Site	Eindhoven		Netherlands
212	1237.5.31008 Boehringer Ingelheim Investigational Site	Harderwijk		Netherlands
213	1237.5.31007 Boehringer Ingelheim Investigational Site	Heerlen		Netherlands
214	1237.5.31010 Boehringer Ingelheim Investigational Site	Hengelo		Netherlands
215	1237.5.31009 Boehringer Ingelheim Investigational Site	Hoorn		Netherlands
216	1237.5.31005 Boehringer Ingelheim Investigational Site	Nieuwegein		Netherlands
217	1237.5.31002 Boehringer Ingelheim Investigational Site	Veldhoven		Netherlands
218	1237.5.31003 Boehringer Ingelheim Investigational Site	Zutphen		Netherlands
219	1237.5.64002 Boehringer Ingelheim Investigational Site	Dunedin		New Zealand
220	1237.5.64001 Boehringer Ingelheim Investigational Site	Greenlane East Auckland NZ		New Zealand
221	1237.5.35105 Boehringer Ingelheim Investigational Site	Amadora		Portugal
222	1237.5.35101 Boehringer Ingelheim Investigational Site	Coimbra		Portugal
223	1237.5.35102 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
224	1237.5.35104 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
225	1237.5.35103 Boehringer Ingelheim Investigational Site	Porto		Portugal
226	1237.5.35106 Boehringer Ingelheim Investigational Site	Vila Nova de Gaia		Portugal
227	1237.5.35107 Boehringer Ingelheim Investigational Site	Viseu		Portugal
228	1237.5.07001 Boehringer Ingelheim Investigational Site	Gatchina (Leningradskaya oblast)		Russian Federation
229	1237.5.07003 Boehringer Ingelheim Investigational Site	Kazan		Russian Federation
230	1237.5.07004 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
231	1237.5.07005 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
232	1237.5.07002 Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
233	1237.5.38601 Boehringer Ingelheim Investigational Site	Golnik		Slovenia
234	1237.5.38602 Boehringer Ingelheim Investigational Site	Golnik		Slovenia
235	1237.5.90003 Boehringer Ingelheim Investigational Site	Istanbul		Turkey
236	1237.5.90004 Boehringer Ingelheim Investigational Site	Istanbul		Turkey
237	1237.5.90002 Boehringer Ingelheim Investigational Site	Izmir		Turkey
238	1237.5.90005 Boehringer Ingelheim Investigational Site	Izmit		Turkey
239	1237.5.90001 Boehringer Ingelheim Investigational Site	Mersin		Turkey

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: NCT01431274
• Other Study ID Numbers: 1237.5; 2009-010668-40
• 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

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	528	525	527	522	522
COMPLETED	431	448	455	462	466
NOT COMPLETED	97	77	72	60	56

Baseline Characteristics

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)	Total
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Total of all reporting groups
Overall Participants	528	525	527	522	522	2624
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.7 (8.0)	64.2 (8.6)	64.2 (8.5)	64.1 (8.0)	64.8 (8.2)	64.2 (8.3)
Sex: Female, Male (Count of Participants)
Female	142 26.9%	133 25.3%	144 27.3%	133 25.5%	138 26.4%	690 26.3%
Male	386 73.1%	392 74.7%	383 72.7%	389 74.5%	384 73.6%	1934 73.7%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.
Description	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.

Outcome Measure Data

Analysis Population Description

The Full analysis set (FAS) included all patients who were randomised, who were dispensed study medication, were documented to have taken any dose of study medication and who had a non-missing baseline and at least one non-missing post-baseline measurement before or at Week 24 for any of the primary and key secondary efficacy endpoints.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.123
	Confidence Interval	(2-Sided) 95%; 0.100 to 0.146
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.117
	Confidence Interval	() 95%; 0.094 to 0.140
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.109
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.132
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.070 to 0.116
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.080 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2169
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.037
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.108
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.130
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5849
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.017 to 0.029
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1863
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.039
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4352
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.032 to 0.014
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

2. Primary Outcome

Title	Trough FEV1 Response on Day 170.
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.059 to 0.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.047 to 0.094
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.058
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.081
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.029
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.052
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.046
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.070
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0407
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; 0.001 to 0.048
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Mean Difference (Final Values)
	Estimated Value	0.053
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.077
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3326
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0151
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95%; 0.006 to 0.053
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1421
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.018
	Confidence Interval	(2-Sided) 95%; -0.041 to 0.006
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

3. Primary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Time Frame	Day 169

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg) Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

5. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 1
Description	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0067
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.056
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.057 to 0.104
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0746
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.022
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.045
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.054 to 0.101
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.070
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.093
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3549
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.011
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.089
	Confidence Interval	(2-Sided) 95%; 0.065 to 0.113
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	-0.048
	Confidence Interval	(2-Sided) 95%; -0.072 to -0.025
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	-0.056
	Confidence Interval	(2-Sided) 95%; -0.080 to -0.033
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5018
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.008
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.032
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

6. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 85
Description	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.128
	Confidence Interval	(2-Sided) 95%; 0.104 to 0.152
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.126
	Confidence Interval	(2-Sided) 95%; 0.102 to 0.150
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.087 to 0.135
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.096
	Confidence Interval	(2-Sided) 95%; 0.072 to 0.120
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.109
	Confidence Interval	(2-Sided) 95%; 0.085 to 0.133
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.017
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.041
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.089 to 0.137
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8834
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.002
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.026
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2129
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.039
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2702
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.013
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.010
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

7. Secondary Outcome

Title	FEV1 AUC(0-3h) Response on Day 365
Description	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.

Outcome Measure Data

Analysis Population Description

FAS (on day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.141
	Confidence Interval	(2-Sided) 95%; 0.117 to 0.166
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.090 to 0.139
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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 0.143
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.099
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.123
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.092
	Confidence Interval	(2-Sided) 95%; 0.067 to 0.117
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0717
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.023
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.047
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.097 to 0.146
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0344
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.027
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.051
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1126
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.045
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6009
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.031
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

8. Secondary Outcome

Title	Trough FEV1 Response on Day 15.
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15

Outcome Measure Data

Analysis Population Description

FAS (day 15). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.072
	Confidence Interval	(2-Sided) 95%; 0.049 to 0.096
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.039 to 0.087
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.047
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.070
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.030
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.054
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.061
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0347
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.049
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.056
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.080
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4407
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.033
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1777
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.016
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.040
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5641
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.017
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

9. Secondary Outcome

Title	Trough FEV1 Response on Day 43
Description	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43.

Outcome Measure Data

Analysis Population Description

FAS (day 43). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.057 to 0.104
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.075
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 95%; 0.014 to 0.062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0517
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; -0.000 to 0.047
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0072
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.056
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.066
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.066
	Confidence Interval	(2-Sided) 95%; 0.042 to 0.090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6619
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.005
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.029
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2401
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.038
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4601
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.033 to 0.015
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.064 to 0.112
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.052 to 0.100
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.070
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.094
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.051
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.075
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.058
	Confidence Interval	(2-Sided) 95%; 0.034 to 0.082
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1405
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.042
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.045 to 0.093
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3118
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.012 to 0.036
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1171
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.019
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.043
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5759
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.017
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

FAS (day 169). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.079
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.103
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.038 to 0.086
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.037 to 0.085
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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 0.071
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.068
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1360
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.042
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.041 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1617
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.041
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2476
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.039
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8083
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.021 to 0.027
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

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 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.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	-0.000 (0.009)	0.028 (0.009)	0.036 (0.009)	0.075 (0.009)	0.099 (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%; 0.075 to 0.124
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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 0.088
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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 0.100
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.048
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.072
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0554
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; -0.001 to 0.048
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.047 to 0.096
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.012
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0041
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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 0.060
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0248
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.004 to 0.053
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5338
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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 0.032
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

13. Secondary Outcome

Title	FVC (Forced Vital Capacity) 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 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.
Measure Participants	525	524	526	521	522
Least Squares Mean (Standard Error) [Litres]	0.350 (0.017)	0.277 (0.017)	0.289 (0.017)	0.400 (0.017)	0.427 (0.017)

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	0.0017
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.029 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.138
	Confidence Interval	(2-Sided) 95%; 0.090 to 0.186
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0426
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.002 to 0.098
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	() 95%; 0.074 to 0.170
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.063 to 0.159
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2661
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.021 to 0.075
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.102 to 0.198
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0119
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.109 to -0.014
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	-0.073
	Confidence Interval	(2-Sided) 95%; -0.121 to -0.025
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6408
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.011
	Confidence Interval	(2-Sided) 95%; -0.036 to 0.059
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

14. Secondary Outcome

Title	FVC (Forced Vital Capacity) 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 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.
Measure Participants	525	524	526	521	522
Least Squares Mean (Standard Error) [Litres]	0.247 (0.017)	0.318 (0.017)	0.275 (0.017)	0.432 (0.017)	0.469 (0.017)

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	0.221
	Confidence Interval	(2-Sided) 95%; 0.173 to 0.270
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.145 to 0.242
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.185
	Confidence Interval	(2-Sided) 95%; 0.136 to 0.233
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.114
	Confidence Interval	(2-Sided) 95%; 0.065 to 0.162
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.157
	Confidence Interval	(2-Sided) 95%; 0.108 to 0.205
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1355
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.012 to 0.085
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.151
	Confidence Interval	(2-Sided) 95%; 0.102 to 0.199
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2562
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.020 to 0.076
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0041
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.022 to 0.119
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0815
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.091 to 0.005
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

15. Secondary Outcome

Title	FVC (Forced Vital Capacity) 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 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.
Measure Participants	525	524	526	521	522
Least Squares Mean (Standard Error) [Litres]	0.212 (0.017)	0.279 (0.017)	0.254 (0.017)	0.386 (0.017)	0.407 (0.017)

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	0.195
	Confidence Interval	(2-Sided) 95%; 0.149 to 0.242
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.107 to 0.199
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.174
	Confidence Interval	(2-Sided) 95%; 0.128 to 0.221
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.107
	Confidence Interval	(2-Sided) 95%; 0.061 to 0.154
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.086 to 0.178
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3727
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.025 to 0.067
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.128
	Confidence Interval	(2-Sided) 95%; 0.082 to 0.175
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0744
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.004 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.021 to 0.114
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2945
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.025
	Confidence Interval	(2-Sided) 95%; -0.071 to 0.022
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

16. Secondary Outcome

Title	FVC (Forced Vital Capacity) 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 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.
Measure Participants	525	524	526	521	522
Least Squares Mean (Standard Error) [Litres]	0.172 (0.018)	0.241 (0.018)	0.221 (0.018)	0.364 (0.018)	0.377 (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	0.205
	Confidence Interval	(2-Sided) 95%; 0.155 to 0.255
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.107 to 0.206
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.192
	Confidence Interval	(2-Sided) 95%; 0.142 to 0.242
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.124
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.174
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.144
	Confidence Interval	(2-Sided) 95%; 0.094 to 0.193
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6103
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.013
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.137
	Confidence Interval	(2-Sided) 95%; 0.087 to 0.186
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0559
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.049
	Confidence Interval	(2-Sided) 95%; -0.001 to 0.098
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.018 to 0.118
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4368
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.070 to 0.030
	Parameter Dispersion	Type: Standard Deviation; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 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.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	0.149 (0.018)	0.222 (0.018)	0.220 (0.018)	0.270 (0.018)	0.296 (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	0.147
	Confidence Interval	(2-Sided) 95%; 0.098 to 0.196
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.027 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.072 to 0.170
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0545
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.001 to 0.097
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0456
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.001 to 0.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2949
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.023 to 0.075
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.074
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.123
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.022 to 0.120
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	0.073
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.122
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9369
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.051 to 0.047
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 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.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	0.150 (0.018)	0.206 (0.018)	0.213 (0.018)	0.254 (0.018)	0.318 (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	0.168
	Confidence Interval	(2-Sided) 95%; 0.119 to 0.217
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.105
	Confidence Interval	(2-Sided) 95%; 0.056 to 0.154
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.054 to 0.152
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0585
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.002 to 0.096
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1042
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.008 to 0.090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.065
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.114
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.063 to 0.161
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0120
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.014 to 0.112
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	0.056
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7889
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.042 to 0.056
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 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.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	0.077 (0.018)	0.168 (0.018)	0.144 (0.018)	0.230 (0.018)	0.265 (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	0.187
	Confidence Interval	(2-Sided) 95%; 0.138 to 0.237
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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%; 0.072 to 0.170
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.103 to 0.202
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0134
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.013 to 0.111
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.086
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.136
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1670
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.015 to 0.084
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.097
	Confidence Interval	(2-Sided) 95%; 0.048 to 0.146
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.066
	Confidence Interval	(2-Sided) 95%; 0.017 to 0.115
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	0.090
	Confidence Interval	(2-Sided) 95%; 0.041 to 0.140
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3332
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.024
	Confidence Interval	(2-Sided) 95%; -0.074 to 0.025
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 23 h and at 23 h 50 min after inhalation of study medication on Day 170

Outcome Measure Data

Analysis Population Description

FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	0.093 (0.017)	0.184 (0.017)	0.169 (0.017)	0.225 (0.017)	0.246 (0.017)

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	0.153
	Confidence Interval	(2-Sided) 95%; 0.105 to 0.201
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.077
	Confidence Interval	(2-Sided) 95%; 0.029 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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%; 0.084 to 0.180
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0926
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.007 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.055
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.103
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3802
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.026 to 0.069
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0105
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; 0.015 to 0.110
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	Method	Mixed Models Analysis
	Comments	Kenward-Roger approximation of denominator degrees of freedom.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; 0.028 to 0.125
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	0.091
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.139
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5554
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.062 to 0.034
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 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.
Measure Participants	519	519	520	518	521
Least Squares Mean (Standard Error) [Litres]	0.014 (0.018)	0.114 (0.018)	0.108 (0.018)	0.155 (0.018)	0.191 (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	0.178
	Confidence Interval	(2-Sided) 95%; 0.127 to 0.228
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.084
	Confidence Interval	(2-Sided) 95%; 0.033 to 0.134
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	0.142
	Confidence Interval	(2-Sided) 95%; 0.091 to 0.192
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1112
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.009 to 0.091
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0632
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.003 to 0.098
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1615
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	0.077
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.127
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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%; 0.044 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	0.101
	Confidence Interval	(2-Sided) 95%; 0.050 to 0.151
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7925
	Comments	Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect.
	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%; -0.057 to 0.044
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tiotropium (5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

22. Secondary Outcome

Title	FEV1 AUC(0-12h) Response in the Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

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

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

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

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

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

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

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

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

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

23. Secondary Outcome

Title	FEV1 AUC(0-24h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

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

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

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

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

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

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

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

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

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

24. Secondary Outcome

Title	FVC AUC(0-12h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

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

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

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

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

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

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

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

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

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

25. Secondary Outcome

Title	FVC AUC(0-24h) Response in Sub-set of Patients With 24-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg).

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

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

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

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

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

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

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

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

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

26. Secondary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm/Group Title	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)
Arm/Group Description	Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg).

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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Time Frame	Day 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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	ANCOVA
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 43 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 85 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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

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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Adjusted 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	Tiotropium (5 µg) versus Tiotropium (2.5 µg). 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 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
Description	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 365 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). 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 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.
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	Tio+Olo FDC (5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 μg) versus Tiotropium (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Olodaterol (5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (5 μg), Tio+Olo FDC (2.5/5 μg)
	Comments
	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	Tio+Olo FDC (2.5/5 μg) versus Tiotropium (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo FDC (2.5/5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tio+Olo FDC (2.5/5 μg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tio+Olo FDC (5/5 μg)
	Comments
	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	Tio+Olo FDC (5/5 µg) versus Tiotropium (2.5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg) Spatial power covariance structure for within-patient errors.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Olodaterol (5 μg), Tiotropium (2.5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tiotropium (2.5 μg), Tiotropium (5 μg)
	Comments
	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	Tiotropium (2.5 µg) versus Olodaterol (5 µg). Spatial power covariance structure for within-patient errors.

Adverse Events

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 447 days)
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
	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	/ (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	75/528 (14.2%)		66/525 (12.6%)		79/527 (15%)		81/522 (15.5%)		87/522 (16.7%)
Blood and lymphatic system disorders
Leukocytosis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lymphadenopathy	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Pancytopenia	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Cardiac disorders
Acute coronary syndrome	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Acute myocardial infarction	1/528 (0.2%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		3/522 (0.6%)
Angina pectoris	1/528 (0.2%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		4/522 (0.8%)
Angina unstable	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Arteriosclerosis coronary artery	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Atrial fibrillation	2/528 (0.4%)		1/525 (0.2%)		2/527 (0.4%)		2/522 (0.4%)		1/522 (0.2%)
Atrioventricular block	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Atrioventricular block complete	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Bradycardia	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cardiac arrest	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Cardiac failure	0/528 (0%)		2/525 (0.4%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cardiac failure acute	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		0/522 (0%)
Cardiac failure chronic	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Cardiac failure congestive	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cardio-respiratory arrest	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Cardiomyopathy	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cardiopulmonary failure	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Coronary artery disease	0/528 (0%)		0/525 (0%)		2/527 (0.4%)		0/522 (0%)		1/522 (0.2%)
Mitral valve stenosis	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Myocardial infarction	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		2/522 (0.4%)
Myocardial ischaemia	0/528 (0%)		0/525 (0%)		2/527 (0.4%)		0/522 (0%)		0/522 (0%)
Ventricular fibrillation	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Ventricular tachycardia	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Ear and labyrinth disorders
Vertigo	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Endocrine disorders
Hyperparathyroidism primary	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Abdominal hernia	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Abdominal pain	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Abdominal pain upper	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		0/522 (0%)
Anal fissure	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Anal fistula	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Coeliac disease	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Crohn's disease	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Diarrhoea	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Diverticular perforation	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Duodenitis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Gastric polyps	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Gastric ulcer	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Gastritis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Gastrointestinal haemorrhage	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Gastrooesophageal reflux disease	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Haematemesis	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Inguinal hernia	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		2/522 (0.4%)		3/522 (0.6%)
Intestinal obstruction	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Large intestine polyp	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Melaena	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Nausea	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Pancreatic cyst	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Pancreatic duct dilatation	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Pancreatitis acute	0/528 (0%)		2/525 (0.4%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Pancreatitis chronic	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Rectal ulcer	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Small intestinal obstruction	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Umbilical hernia	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Vomiting	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
General disorders
Chest pain	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		1/522 (0.2%)
Death	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		1/522 (0.2%)
Electrocution	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Generalised oedema	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Hernia	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Inflammation	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Local swelling	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Malaise	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Multi-organ failure	0/528 (0%)		0/525 (0%)		2/527 (0.4%)		0/522 (0%)		0/522 (0%)
Non-cardiac chest pain	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Sudden death	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Systemic inflammatory response syndrome	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Hepatobiliary disorders
Bile duct obstruction	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Bile duct stone	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Biliary dilatation	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Cholangitis	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Cholecystitis acute	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Hepatic cyst	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Jaundice cholestatic	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Infections and infestations
Appendicitis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Bronchitis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		1/522 (0.2%)
Bronchopneumonia	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cellulitis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Clostridium difficile colitis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cystitis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Diverticulitis	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Extradural abscess	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Gastroenteritis	3/528 (0.6%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Hepatitis E	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Infected bites	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Infective exacerbation of chronic obstructive airways disease	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Influenza	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Klebsiella sepsis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Lobar pneumonia	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		3/522 (0.6%)		1/522 (0.2%)
Localised infection	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lung abscess	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lung infection	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Otitis media chronic	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Pneumonia	8/528 (1.5%)		5/525 (1%)		5/527 (0.9%)		10/522 (1.9%)		9/522 (1.7%)
Pneumonia bacterial	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Pneumonia pneumococcal	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Pyelonephritis	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Respiratory tract infection	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Sepsis	0/528 (0%)		2/525 (0.4%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Septic shock	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Sinusitis	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Staphylococcal sepsis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Urinary tract infection	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Ankle fracture	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Bone fissure	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Brain contusion	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Cervical vertebral fracture	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Clavicle fracture	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Contusion	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Facial bones fracture	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Fall	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		2/522 (0.4%)		2/522 (0.4%)
Femoral neck fracture	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Femur fracture	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		2/522 (0.4%)		0/522 (0%)
Fractured coccyx	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Humerus fracture	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Ligament sprain	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Limb injury	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Meniscus injury	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Periprosthetic fracture	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Pneumothorax traumatic	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Post laminectomy syndrome	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Postoperative ileus	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Procedural pain	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Radius fracture	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Road traffic accident	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Skull fractured base	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Subdural haematoma	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Subdural haemorrhage	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Tendon rupture	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Thermal burn	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Thoracic vertebral fracture	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Wound	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Investigations
Arteriogram coronary	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cardiac murmur	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Prostatic specific antigen increased	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Failure to thrive	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Fluid overload	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Gout	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Hyperkalaemia	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		2/522 (0.4%)
Hypoglycaemia	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Hyponatraemia	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Hypovolaemia	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Back pain	0/528 (0%)		0/525 (0%)		0/527 (0%)		2/522 (0.4%)		0/522 (0%)
Bone pain	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Fascial hernia	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Intervertebral disc protrusion	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lumbar spinal stenosis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Musculoskeletal pain	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Osteoarthritis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Osteoporosis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Spinal column stenosis	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma pancreas	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Basal cell carcinoma	1/528 (0.2%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Benign neoplasm of bladder	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Benign ovarian tumour	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Bladder cancer	1/528 (0.2%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Bladder neoplasm	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Bladder papilloma	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Brain neoplasm	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Bronchial carcinoma	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Chronic lymphocytic leukaemia	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Colon cancer	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Enchondroma	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Gastric cancer	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		2/522 (0.4%)		0/522 (0%)
Gastric neoplasm	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Glioblastoma multiforme	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Hepatic cancer	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Lipoma	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Lung adenocarcinoma	1/528 (0.2%)		1/525 (0.2%)		2/527 (0.4%)		0/522 (0%)		0/522 (0%)
Lung adenocarcinoma metastatic	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Lung cancer metastatic	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Lung neoplasm malignant	1/528 (0.2%)		1/525 (0.2%)		5/527 (0.9%)		3/522 (0.6%)		1/522 (0.2%)
Malignant melanoma	0/528 (0%)		0/525 (0%)		2/527 (0.4%)		0/522 (0%)		0/522 (0%)
Meningioma	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Metastases to bone	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Metastases to central nervous system	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Metastases to lymph nodes	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Neuroendocrine carcinoma of the skin	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Oesophageal carcinoma	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Prostate cancer	2/528 (0.4%)		1/525 (0.2%)		2/527 (0.4%)		2/522 (0.4%)		0/522 (0%)
Renal cancer	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Renal cell carcinoma	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Small cell lung cancer	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Small cell lung cancer metastatic	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Squamous cell carcinoma of skin	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Tongue neoplasm malignant stage unspecified	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Ureteric cancer	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Nervous system disorders
Amyotrophic lateral sclerosis	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cerebral infarction	1/528 (0.2%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Cerebrovascular accident	2/528 (0.4%)		2/525 (0.4%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Convulsion	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Critical illness polyneuropathy	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Cubital tunnel syndrome	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Dementia	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Dizziness	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Epilepsy	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Haemorrhagic stroke	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Intracranial aneurysm	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Ischaemic stroke	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lacunar infarction	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Lumbar radiculopathy	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Migraine	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Multiple sclerosis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Neuralgia	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Post herpetic neuralgia	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Sciatica	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Syncope	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Transient ischaemic attack	0/528 (0%)		2/525 (0.4%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Vocal cord paralysis	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Psychiatric disorders
Abnormal behaviour	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Bipolar disorder	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Confusional state	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Depression	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Major depression	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Psychiatric decompensation	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Psychotic disorder	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Suicidal ideation	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Suicide attempt	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Renal and urinary disorders
Calculus ureteric	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Haematuria	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Nephrolithiasis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Renal colic	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Renal failure acute	2/528 (0.4%)		0/525 (0%)		2/527 (0.4%)		1/522 (0.2%)		0/522 (0%)
Renal failure chronic	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Urethral stenosis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Urinary retention	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		1/522 (0.2%)
Urinary tract obstruction	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/528 (0.4%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		1/522 (0.2%)
Menorrhagia	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Pelvic adhesions	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Prostatitis	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Prostatomegaly	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Uterine prolapse	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Asthma	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Bronchospasm	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Chronic obstructive pulmonary disease	27/528 (5.1%)		25/525 (4.8%)		24/527 (4.6%)		20/522 (3.8%)		36/522 (6.9%)
Dyspnoea	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		1/522 (0.2%)
Haemoptysis	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Hypercapnia	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Hypoxia	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		0/522 (0%)
Lung infiltration	0/528 (0%)		1/525 (0.2%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Organising pneumonia	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Pleural effusion	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		0/522 (0%)
Pneumonitis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Pneumothorax	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Pneumothorax spontaneous	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Pulmonary congestion	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Pulmonary embolism	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		3/522 (0.6%)
Pulmonary hypertension	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Pulmonary mass	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		1/522 (0.2%)
Pulmonary oedema	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Respiratory distress	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Respiratory failure	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Skin and subcutaneous tissue disorders
Psoriasis	0/528 (0%)		0/525 (0%)		0/527 (0%)		1/522 (0.2%)		0/522 (0%)
Surgical and medical procedures
Hip arthroplasty	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Nasal septal operation	0/528 (0%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Vascular disorders
Arterial occlusive disease	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Arteriosclerosis	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Circulatory collapse	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Deep vein thrombosis	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Hypertension	2/528 (0.4%)		0/525 (0%)		1/527 (0.2%)		1/522 (0.2%)		0/522 (0%)
Hypertensive crisis	0/528 (0%)		0/525 (0%)		1/527 (0.2%)		0/522 (0%)		0/522 (0%)
Hypotension	0/528 (0%)		1/525 (0.2%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
Peripheral arterial occlusive disease	1/528 (0.2%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		0/522 (0%)
Peripheral vascular disorder	2/528 (0.4%)		0/525 (0%)		0/527 (0%)		0/522 (0%)		1/522 (0.2%)
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	221/528 (41.9%)		207/525 (39.4%)		210/527 (39.8%)		211/522 (40.4%)		193/522 (37%)
Infections and infestations
Nasopharyngitis	65/528 (12.3%)		64/525 (12.2%)		67/527 (12.7%)		64/522 (12.3%)		67/522 (12.8%)
Upper respiratory tract infection	24/528 (4.5%)		30/525 (5.7%)		30/527 (5.7%)		40/522 (7.7%)		25/522 (4.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	155/528 (29.4%)		144/525 (27.4%)		151/527 (28.7%)		133/522 (25.5%)		134/522 (25.7%)

Limitations/Caveats

[Not Specified]

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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.