12 / 48 wk Pivotal PFT vs PBO in COPD II

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00782509
• Collaborator: (none)
• Enrollment: 644
• Locations: 51
• Arms: 3
• Patients Per Site: 12.6

Study Details

Study Description

Brief Summary

This primary objective of this study is to compare two doses of BI 1744 CL inhalation solution delivered by the Respimat® inhaler once daily to placebo in patients with chronic obstructive pulmonary disease (COPD).

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Olodaterol (BI 1744); Drug: Olodaterol (BI 1744); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 644 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 mcg [2 Actuations of 2.5 mcg] and 10 mcg [2 Actuations of 5 mcg]) Delivered by the Respimat® Inhaler, in Patients With Chronic Obstructive Pulmonary Disease (COPD
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olodaterol (BI1744) Low Low dose inhaled orally once daily from the Respimat inhaler	Drug: Olodaterol (BI 1744); Comparison of low and high doses on efficacy and safety in COPD patients
Placebo Comparator: Placebo Olodaterol (BI 1744) placebo inhaled orally once daily from the Respimat inhaler	Drug: Placebo; Olodaterol (BI 1744) placebo inhaled orally once daily from the Respimat inhaler
Experimental: Olodaterol (BI 1744) High High dose inhaled orally once daily from the Respimat inhaler	Drug: Olodaterol (BI 1744); Comparison of low and high doses on efficacy and safety in COPD patients

Outcome Measures

Primary Outcome Measures

1. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at Day 85 (12 Weeks) [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Day 85]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

2. Trough FEV1 Response at Day 85 (12 Weeks) [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h and - 10 mins prior to study drug at Day 85.]

   Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

Secondary Outcome Measures

1. Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks) [1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)]

   Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.

2. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response At Day 1 [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

3. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 2 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

4. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 6 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -1h, -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

5. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 24 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

6. Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 48 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks]

   Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

7. Trough FEV1 Response After 2 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks]

   Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed a -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

8. Trough FEV1 Response After 6 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks]

   Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

9. Trough FEV1 Response After 18 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks]

   Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

10. Trough FEV1 Response After 24 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks]

    Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

11. Trough FEV1 Response After 32 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks]

    Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

12. Trough FEV1 Response After 40 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks]

    Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

13. Trough FEV1 Response After 48 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks]

    Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

14. Peak FEV1 (0-3h) Response At Day 1 [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

15. Peak FEV1 (0-3h) Response After 2 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

16. Peak FEV1 (0-3h) Response After 6 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

17. Peak FEV1 (0-3h) Response After 12 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

18. Peak FEV1 (0-3h) Response After 24 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

19. Peak FEV1 (0-3h) Response After 48 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks]

    Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

20. Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response At Day 1 [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

21. Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response After 2 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

22. FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 6 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

23. FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 12 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

24. FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 24 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

25. FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 48 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks]

    Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

26. Trough FVC Response After 2 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

27. Trough FVC Response After 6 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

28. Trough FVC Response After 12 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 12 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

29. Trough FVC Response After 18 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

30. Trough FVC Response After 24 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

31. Trough FVC Response After 32 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

32. Trough FVC Response After 40 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

33. Trough FVC Response After 48 Weeks [1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks]

    Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

34. FVC Peak (0-3h) Response At Day 1 [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours aftertreatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

35. FVC Peak (0-3h) Response After 2 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

36. FVC Peak (0-3h) Response After 6 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

37. FVC Peak (0-3h) Response After 12 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

38. FVC Peak (0-3h) Response After 24 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

39. FVC Peak (0-3h) Response After 48 Weeks [1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks]

    Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

40. Forced Vital Capacity (FVC) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks) [1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)]

    Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FVC AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.

41. Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEF) [immediately upon arising (before drug administration) from Screening to week 48]

    Weekly mean pre-dose morning peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded.

42. Weekly Mean Evening Peak Expiratory Flow Rate (PEF) [at bedtime from Screening to week 48]

    Weekly mean evening peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded.

43. Weekly Mean of Daily Daytime Rescue Use [Week 48]

    The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each day during week 48.

44. Weekly Mean of Daily Nighttime Rescue Use [Week 48]

    The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each night during week 48.

45. Weekly Mean of Daily (24h) Rescue Use [Week 48]

    The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each 24 hour period during week 48.

46. Patient's Global Rating at Week 6 [Week 6 visit]

    Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.

47. Patient's Global Rating at Week 12 [Week 12 visit]

    Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.

48. Patient's Global Rating at Week 24 [Week 24 visit]

    Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.

49. Patient's Global Rating at Week 48 [Week 48 visit]

    Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.

50. Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [Baseline to end of study at 48 weeks.]

    Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval.

51. Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization [Baseline to end of study at 48 weeks.]

    Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval.

52. Time to First Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [Baseline to end of study at 48 weeks.]

    Qualifying events of COPD were specifically pre-defined in the protocol.Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval..

53. Number of COPD Exacerbations [Baseline to end of study at week 48 visit]

    Mean number of COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria.

54. Number of COPD Exacerbations Requiring Hospitalization [Baseline to end of study at week 48 visit]

    Mean number of COPD exacerbations requiring hospitalization per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization.

55. Number of Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbations [Baseline to end of study at 48 weeks.]

    Mean number of moderate COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids.

56. Changes in Safety Parameters Related to Treatment [48 weeks]

    Occurence of bronchoconstriction, cardiac disorders and investigations related to treatment. Bronchoconstriction is defined as any of the following events: Drop in trough FEV1 >= 15%, Rescue medication use within 30 min of inhaling randomized treatment on a clinic test day or Cough, wheeze, or dyspnoea AE within 30 min of inhaling randomized treatment on a clinic test day.

57. Change From Baseline in Potassium [Day 1 and at 12, 24 and 48 weeks]

    Laboratory testing: Average change from baseline of potassium measured. The laboratory tests at Day 1 were considered the baseline measurements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• All patients must have a diagnosis of chronic obstructive pulmonary disease

• Male or female patients, 40 years of age or older Patients must be current or ex-smokers with a smoking history of more than 10 pack years Post bronchodilator FEV1 <80% predicted and post-bronchodilator FEV1/FVC <70%

Exclusion criteria:

• Patients with a significant disease other than COPD

• Patients with a history of asthma

• Patients with any of the following conditions:

a history of myocardial infarction within 1 year of screening visit (Visit 1) unstable or life-threatening cardiac arrhythmia. have been hospitalized for heart failure within the past year. known active tuberculosis a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed) a history of life-threatening pulmonary obstruction a history of cystic fibrosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1222.12.1227 Boehringer Ingelheim Investigational Site	Mobile	Alabama	United States
2	1222.12.1218 Boehringer Ingelheim Investigational Site	Wheat Ridge	Colorado	United States
3	1222.12.1226 Boehringer Ingelheim Investigational Site	Wheat Ridge	Colorado	United States
4	1222.12.1214 Boehringer Ingelheim Investigational Site	Waterbury	Connecticut	United States
5	1222.12.1207 Boehringer Ingelheim Investigational Site	Clearwater	Florida	United States
6	1222.12.1224 Boehringer Ingelheim Investigational Site	Panama City	Florida	United States
7	1222.12.1222 Boehringer Ingelheim Investigational Site	Tampa	Florida	United States
8	1222.12.1208 Boehringer Ingelheim Investigational Site	Winter Park	Florida	United States
9	1222.12.1220 Boehringer Ingelheim Investigational Site	River Forest	Illinois	United States
10	1222.12.1229 Boehringer Ingelheim Investigational Site	New Orleans	Louisiana	United States
11	1222.12.1219 Boehringer Ingelheim Investigational Site	Ann Arbor	Michigan	United States
12	1222.12.1209 Boehringer Ingelheim Investigational Site	Livonia	Michigan	United States
13	1222.12.1233 Boehringer Ingelheim Investigational Site	Henderson	Nevada	United States
14	1222.12.1228 Boehringer Ingelheim Investigational Site	Summit	New Jersey	United States
15	1222.12.1206 Boehringer Ingelheim Investigational Site	Albuquerque	New Mexico	United States
16	1222.12.1205 Boehringer Ingelheim Investigational Site	Rochester	New York	United States
17	1222.12.1213 Boehringer Ingelheim Investigational Site	Elizabeth City	North Carolina	United States
18	1222.12.1223 Boehringer Ingelheim Investigational Site	Harrisburg	North Carolina	United States
19	1222.12.1217 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina	United States
20	1222.12.1203 Boehringer Ingelheim Investigational Site	Cincinnatti	Ohio	United States
21	1222.12.1201 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania	United States
22	1222.12.1230 Boehringer Ingelheim Investigational Site	Easley	South Carolina	United States
23	1222.12.1216 Boehringer Ingelheim Investigational Site	Greenville	South Carolina	United States
24	1222.12.1221 Boehringer Ingelheim Investigational Site	Dallas	Texas	United States
25	1222.12.1212 Boehringer Ingelheim Investigational Site	Danville	Virginia	United States
26	1222.12.1211 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
27	1222.12.1225 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
28	1222.12.1232 Boehringer Ingelheim Investigational Site	Morgantown	West Virginia	United States
29	1222.12.1298 Boehringer Ingelheim Investigational Site	Beijing		China
30	1222.12.1301 Boehringer Ingelheim Investigational Site	Chongqing		China
31	1222.12.1305 Boehringer Ingelheim Investigational Site	Guangzhou		China
32	1222.12.1306 Boehringer Ingelheim Investigational Site	Haikou		China
33	1222.12.1302 Boehringer Ingelheim Investigational Site	Hangzhou		China
34	1222.12.1304 Boehringer Ingelheim Investigational Site	Nanjing		China
35	1222.12.1296 Boehringer Ingelheim Investigational Site	Shanghai		China
36	1222.12.1297 Boehringer Ingelheim Investigational Site	Shanghai		China
37	1222.12.1303 Boehringer Ingelheim Investigational Site	Wuhan		China
38	1222.12.1299 Boehringer Ingelheim Investigational Site	Xi'An		China
39	1222.12.1300 Boehringer Ingelheim Investigational Site	Xi'An		China
40	1222.12.1269 Boehringer Ingelheim Investigational Site	Berlin		Germany
41	1222.12.1270 Boehringer Ingelheim Investigational Site	Berlin		Germany
42	1222.12.1271 Boehringer Ingelheim Investigational Site	Berlin		Germany
43	1222.12.1268 Boehringer Ingelheim Investigational Site	Hamburg		Germany
44	1222.12.1266 Boehringer Ingelheim Investigational Site	Koblenz		Germany
45	1222.12.1272 Boehringer Ingelheim Investigational Site	Mannheim		Germany
46	1222.12.1267 Boehringer Ingelheim Investigational Site	Rüdersdorf		Germany
47	1222.12.1289 Boehringer Ingelheim Investigational Site	Kaohsiung County		Taiwan
48	1222.12.1290 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
49	1222.12.1288 Boehringer Ingelheim Investigational Site	Taichung		Taiwan
50	1222.12.1287 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
51	1222.12.1286 Boehringer Ingelheim Investigational Site	Taoyuan		Taiwan

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00782509
• Other Study ID Numbers: 1222.12; 2008-003704-67
• First Posted: Oct 31, 2008
• Last Update Posted: Jun 27, 2014
• Last Verified: Jun 1, 2014

• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive; Olodaterol

Study Results

Participant Flow

Pre-assignment Detail	644 patients were randomised into the study, however two of the patients were not treated.

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Period Title: Overall Study
STARTED	216	209	217
COMPLETED	175	185	181
NOT COMPLETED	41	24	36

Baseline Characteristics

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd	Total
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Total of all reporting groups
Overall Participants	216	209	217	642
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.8 (8.3)	64.7 (8.1)	65.4 (9.7)	64.6 (8.8)
Sex: Female, Male (Count of Participants)
Female	64 29.6%	57 27.3%	65 30%	186 29%
Male	152 70.4%	152 72.7%	152 70%	456 71%
Tiotropium (Tio) Use Stratum (Number of participants) [Number]
Non-tiotropium	175 81%	170 81.3%	173 79.7%	518 80.7%
Tiotropium	41 19%	39 18.7%	44 20.3%	124 19.3%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at Day 85 (12 Weeks)
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Day 85

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS). FAS is defined as all randomized patients who received at least one dose of treatment and had both baseline data and at least one post-baseline measurement at or before Day 85 (12 weeks) for either co-primary efficacy variable.

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.008 (0.013)	0.159 (0.013)	0.152 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.151
	Confidence Interval	() 95%; 0.116 to 0.185
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.143
	Confidence Interval	() 95%; 0.110 to 0.177
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 10 mcg qd minus Placebo

2. Primary Outcome

Title	Trough FEV1 Response at Day 85 (12 Weeks)
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h and - 10 mins prior to study drug at Day 85.

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.003 (0.014)	0.044 (0.014)	0.045 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0116
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.047
	Confidence Interval	() 95%; 0.011 to 0.084
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0095
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	() 95%; 0.012 to 0.085
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

3. Secondary Outcome

Title	Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
Description	Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)

Outcome Measure Data

Analysis Population Description

Patients in FAS with spirometry data after 3 hours at Visit 5 (12-hour pulmonary function test set)

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	98	116	107
Mean (Standard Error) [Liter]	0.010 (0.021)	0.120 (0.020)	0.100 (0.020)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Treatment, tiotropium stratum and baseline as fixed effects
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.110
	Confidence Interval	() 95%; 0.057 to 0.162
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment, tiotropium stratum and baseline as fixed effects
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.089
	Confidence Interval	() 95%; 0.036 to 0.143
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Olo 10 mcg qd minus Placebo

4. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response At Day 1
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.025 (0.013)	0.189 (0.013)	0.196 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.164
	Confidence Interval	() 95%; 0.131 to 0.197
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.171
	Confidence Interval	() 95%; 0.138 to 0.204
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 10 mcg qd minus Placebo

5. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.025 (0.013)	0.188 (0.013)	0.177 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.163
	Confidence Interval	() 95%; 0.130 to 0.197
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.152
	Confidence Interval	() 95%; 0.119 to 0.186
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 10 mcg qd minus Placebo

6. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -1h, -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.010 (0.013)	0.180 (0.013)	0.171 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.169
	Confidence Interval	() 95%; 0.135 to 0.203
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.161
	Confidence Interval	() 95%; 0.127 to 0.195
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Olo 10 mcg qd minus Placebo

7. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	-0.010 (0.013)	0.155 (0.013)	0.126 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.165
	Confidence Interval	() 95%; 0.131 to 0.200
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.136
	Confidence Interval	() 95%; 0.102 to 0.171
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

8. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	-0.030 (0.013)	0.132 (0.013)	0.128 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.161
	Confidence Interval	() 95%; 0.127 to 0.196
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.158
	Confidence Interval	() 95%; 0.123 to 0.193
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.013
	Estimation Comments	Olo 10 mcg qd minus Placebo

9. Secondary Outcome

Title	Trough FEV1 Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed a -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.013 (0.014)	0.066 (0.014)	0.078 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.053
	Confidence Interval	() 95%; 0.017 to 0.089
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.065
	Confidence Interval	() 95%; 0.028 to 0.101
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

10. Secondary Outcome

Title	Trough FEV1 Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.002 (0.014)	0.071 (0.014)	0.082 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.073
	Confidence Interval	() 95%; 0.037 to 0.110
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.085
	Confidence Interval	() 95%; 0.049 to 0.121
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

11. Secondary Outcome

Title	Trough FEV1 Response After 18 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.007 (0.014)	0.062 (0.014)	0.037 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.069
	Confidence Interval	() 95%; 0.032 to 0.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.044
	Confidence Interval	() 95%; 0.007 to 0.081
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

12. Secondary Outcome

Title	Trough FEV1 Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.036 (0.014)	0.033 (0.014)	0.022 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.069
	Confidence Interval	() 95%; 0.032 to 0.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.058
	Confidence Interval	() 95%; 0.021 to 0.095
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

13. Secondary Outcome

Title	Trough FEV1 Response After 32 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.029 (0.014)	0.029 (0.014)	-0.002 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.058
	Confidence Interval	() 95%; 0.020 to 0.095
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1614
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.027
	Confidence Interval	() 95%; -0.011 to 0.064
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

14. Secondary Outcome

Title	Trough FEV1 Response After 40 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.029 (0.014)	0.033 (0.014)	0.043 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.062
	Confidence Interval	() 95%; 0.025 to 0.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.072
	Confidence Interval	() 95%; 0.034 to 0.109
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

15. Secondary Outcome

Title	Trough FEV1 Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.057 (0.014)	0.011 (0.014)	0.014 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	() 95%; 0.031 to 0.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.071
	Confidence Interval	() 95%; 0.033 to 0.108
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

16. Secondary Outcome

Title	Peak FEV1 (0-3h) Response At Day 1
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.099 (0.014)	0.267 (0.014)	0.276 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.168
	Confidence Interval	() 95%; 0.132 to 0.203
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.177
	Confidence Interval	() 95%; 0.142 to 0.212
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

17. Secondary Outcome

Title	Peak FEV1 (0-3h) Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.104 (0.014)	0.259 (0.014)	0.251 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.155
	Confidence Interval	() 95%; 0.119 to 0.190
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.147
	Confidence Interval	() 95%; 0.111 to 0.182
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

18. Secondary Outcome

Title	Peak FEV1 (0-3h) Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.080 (0.014)	0.252 (0.014)	0.246 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.172
	Confidence Interval	() 95%; 0.136 to 0.209
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.166
	Confidence Interval	() 95%; 0.130 to 0.202
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

19. Secondary Outcome

Title	Peak FEV1 (0-3h) Response After 12 Weeks
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.088 (0.014)	0.232 (0.014)	0.217 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.144
	Confidence Interval	() 95%; 0.108 to 0.180
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.130
	Confidence Interval	() 95%; 0.094 to 0.166
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Olo 10 mcg qd minus Placebo

20. Secondary Outcome

Title	Peak FEV1 (0-3h) Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.062 (0.014)	0.226 (0.014)	0.197 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.164
	Confidence Interval	() 95%; 0.128 to 0.201
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.135
	Confidence Interval	() 95%; 0.098 to 0.171
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

21. Secondary Outcome

Title	Peak FEV1 (0-3h) Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.041 (0.014)	0.197 (0.014)	0.198 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.155
	Confidence Interval	() 95%; 0.118 to 0.192
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.157
	Confidence Interval	() 95%; 0.120 to 0.194
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019
	Estimation Comments	Olo 10 mcg qd minus Placebo

22. Secondary Outcome

Title	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response At Day 1
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.052 (0.026)	0.383 (0.026)	0.384 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.331
	Confidence Interval	() 95%; 0.263 to 0.399
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.333
	Confidence Interval	() 95%; 0.265 to 0.400
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments	Olo 10 mcg qd minus Placebo

23. Secondary Outcome

Title	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.096 (0.026)	0.338 (0.026)	0.323 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.242
	Confidence Interval	() 95%; 0.174 to 0.310
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.226
	Confidence Interval	() 95%; 0.159 to 0.294
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 10 mcg qd minus Placebo

24. Secondary Outcome

Title	FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.048 (0.026)	0.312 (0.027)	0.294 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.263
	Confidence Interval	() 95%; 0.195 to 0.332
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.246
	Confidence Interval	() 95%; 0.178 to 0.315
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 10 mcg qd minus Placebo

25. Secondary Outcome

Title	FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 12 Weeks
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.046 (0.026)	0.284 (0.027)	0.291 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.239
	Confidence Interval	() 95%; 0.170 to 0.308
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.245
	Confidence Interval	() 95%; 0.176 to 0.314
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 10 mcg qd minus Placebo

26. Secondary Outcome

Title	FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.062 (0.027)	0.303 (0.027)	0.281 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.241
	Confidence Interval	() 95%; 0.171 to 0.311
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.219
	Confidence Interval	() 95%; 0.150 to 0.289
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.035
	Estimation Comments	Olo 10 mcg qd minus Placebo

27. Secondary Outcome

Title	FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.053 (0.027)	0.271 (0.027)	0.271 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.217
	Confidence Interval	() 95%; 0.147 to 0.288
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.218
	Confidence Interval	() 95%; 0.148 to 0.288
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 10 mcg qd minus Placebo

28. Secondary Outcome

Title	Trough FVC Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.054 (0.028)	0.113 (0.028)	0.141 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1040
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	() 95%; -0.012 to 0.131
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0172
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.087
	Confidence Interval	() 95%; 0.015 to 0.158
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 10 mcg qd minus Placebo

29. Secondary Outcome

Title	Trough FVC Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.029 (0.028)	0.122 (0.028)	0.147 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0106
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.094
	Confidence Interval	() 95%; 0.022 to 0.166
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.118
	Confidence Interval	() 95%; 0.046 to 0.190
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

30. Secondary Outcome

Title	Trough FVC Response After 12 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.043 (0.028)	0.075 (0.028)	0.091 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3821
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	() 95%; -0.040 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1917
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	() 95%; -0.024 to 0.120
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

31. Secondary Outcome

Title	Trough FVC Response After 18 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.064 (0.028)	0.114 (0.028)	0.098 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1808
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	() 95%; -0.023 to 0.123
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3700
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.033
	Confidence Interval	() 95%; -0.039 to 0.106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

32. Secondary Outcome

Title	Trough FVC Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.021 (0.028)	0.066 (0.028)	0.091 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2312
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.045
	Confidence Interval	() 95%; -0.029 to 0.118
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0596
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.070
	Confidence Interval	() 95%; -0.003 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

33. Secondary Outcome

Title	Trough FVC Response After 32 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.061 (0.028)	0.099 (0.028)	0.058 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3110
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.038
	Confidence Interval	() 95%; -0.036 to 0.111
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9426
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.003
	Confidence Interval	() 95%; -0.076 to 0.071
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Olo 10 mcg qd minus Placebo

34. Secondary Outcome

Title	Trough FVC Response After 40 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	0.062 (0.028)	0.104 (0.028)	0.131 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2680
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.042
	Confidence Interval	() 95%; -0.032 to 0.115
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0662
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.069
	Confidence Interval	() 95%; -0.005 to 0.143
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Olo 10 mcg qd minus Placebo

35. Secondary Outcome

Title	Trough FVC Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	205	205	207
Mean (Standard Error) [Liter]	-0.008 (0.028)	0.038 (0.028)	0.054 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2249
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.046
	Confidence Interval	() 95%; -0.028 to 0.120
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0994
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.062
	Confidence Interval	() 95%; -0.012 to 0.136
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Olo 10 mcg qd minus Placebo

36. Secondary Outcome

Title	FVC Peak (0-3h) Response At Day 1
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours aftertreatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.202 (0.027)	0.534 (0.028)	0.535 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.332
	Confidence Interval	() 95%; 0.261 to 0.403
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.333
	Confidence Interval	() 95%; 0.263 to 0.403
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 10 mcg qd minus Placebo

37. Secondary Outcome

Title	FVC Peak (0-3h) Response After 2 Weeks
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.254 (0.027)	0.479 (0.028)	0.464 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.225
	Confidence Interval	() 95%; 0.153 to 0.296
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.210
	Confidence Interval	() 95%; 0.139 to 0.281
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	Olo 10 mcg qd minus Placebo

38. Secondary Outcome

Title	FVC Peak (0-3h) Response After 6 Weeks
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.183 (0.028)	0.451 (0.028)	0.434 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.268
	Confidence Interval	() 95%; 0.196 to 0.340
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.251
	Confidence Interval	() 95%; 0.179 to 0.323
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

39. Secondary Outcome

Title	FVC Peak (0-3h) Response After 12 Weeks
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.213 (0.028)	0.439 (0.028)	0.422 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.226
	Confidence Interval	() 95%; 0.154 to 0.298
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.209
	Confidence Interval	() 95%; 0.137 to 0.281
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

40. Secondary Outcome

Title	FVC Peak (0-3h) Response After 24 Weeks
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.223 (0.028)	0.449 (0.028)	0.429 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.226
	Confidence Interval	() 95%; 0.153 to 0.299
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.206
	Confidence Interval	() 95%; 0.133 to 0.279
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

41. Secondary Outcome

Title	FVC Peak (0-3h) Response After 48 Weeks
Description	Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	207	215
Mean (Standard Error) [Liter]	0.208 (0.028)	0.415 (0.028)	0.419 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.207
	Confidence Interval	() 95%; 0.133 to 0.280
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model with trt,tio stratum,visit,trt-by-visit as fixed effects,baseline, baseline-by-visit as fixed covariates, patient as random effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.211
	Confidence Interval	() 95%; 0.138 to 0.285
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Olo 10 mcg qd minus Placebo

42. Secondary Outcome

Title	Forced Vital Capacity (FVC) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
Description	Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FVC AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time Frame	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)

Outcome Measure Data

Analysis Population Description

Patients in FAS with spirometry data after 3 hours at Visit 5 (12-hour pulmonary function test set)

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	98	116	107
Mean (Standard Error) [Liter]	0.057 (0.036)	0.199 (0.035)	0.212 (0.036)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments
	Method	ANCOVA
	Comments	Treatment, tiotropium stratum and baseline as fixed effects
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.142
	Confidence Interval	() 95%; 0.049 to 0.235
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	ANCOVA
	Comments	Treatment, tiotropium stratum and baseline as fixed effects
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.156
	Confidence Interval	() 95%; 0.061 to 0.250
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments	Olo 10 mcg qd minus Placebo

43. Secondary Outcome

Title	Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEF)
Description	Weekly mean pre-dose morning peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded.
Time Frame	immediately upon arising (before drug administration) from Screening to week 48

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	211	204	214
Mean (Standard Error) [L/min]	182.939 (3.800)	196.300 (3.868)	203.873 (3.757)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0072
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	13.360
	Confidence Interval	(2-Sided) 95%; 3.622 to 23.099
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.959
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.934
	Confidence Interval	(2-Sided) 95%; 11.323 to 30.545
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.894
	Estimation Comments

44. Secondary Outcome

Title	Weekly Mean Evening Peak Expiratory Flow Rate (PEF)
Description	Weekly mean evening peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded.
Time Frame	at bedtime from Screening to week 48

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	213	205	215
Mean (Standard Error) [L/min]	195.502 (3.987)	207.958 (4.065)	216.155 (3.948)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0169
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	12.456
	Confidence Interval	(2-Sided) 95%; 2.242 to 22.670
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.201
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.653
	Confidence Interval	(2-Sided) 95%; 10.574 to 30.731
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.132
	Estimation Comments

45. Secondary Outcome

Title	Weekly Mean of Daily Daytime Rescue Use
Description	The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each day during week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	205	215
Mean (Standard Error) [Number of puffs]	1.363 (0.097)	0.947 (0.099)	0.850 (0.097)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.416
	Confidence Interval	(2-Sided) 95%; -0.665 to -0.167
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.127
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.513
	Confidence Interval	(2-Sided) 95%; -0.760 to -0.267
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.125
	Estimation Comments

46. Secondary Outcome

Title	Weekly Mean of Daily Nighttime Rescue Use
Description	The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each night during week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	205	215
Mean (Standard Error) [Number of puffs]	2.072 (0.121)	1.652 (0.123)	1.312 (0.120)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.420
	Confidence Interval	(2-Sided) 95%; -0.729 to -0.111
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.157
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.760
	Confidence Interval	() 95%; -1.065 to -0.456
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.155
	Estimation Comments

47. Secondary Outcome

Title	Weekly Mean of Daily (24h) Rescue Use
Description	The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each 24 hour period during week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	215	205	215
Mean (Standard Error) [Number of puffs]	3.436 (0.193)	2.599 (0.197)	2.158 (0.192)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.837
	Confidence Interval	(2-Sided) 95%; -1.333 to -0.342
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.252
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	non-MMRM ANCOVA models with treatment, tiotropium strata and baseline as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.278
	Confidence Interval	(2-Sided) 95%; -1.767 to -0.789
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.249
	Estimation Comments

48. Secondary Outcome

Title	Patient's Global Rating at Week 6
Description	Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.
Time Frame	Week 6 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	196	202	205
Mean (Standard Error) [Point on scale]	3.3 (0.1)	3.0 (0.1)	2.9 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	() 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 10 mcg qd minus Placebo

49. Secondary Outcome

Title	Patient's Global Rating at Week 12
Description	Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.
Time Frame	Week 12 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	196	202	205
Mean (Standard Error) [Point on scale]	3.2 (0.1)	2.9 (0.1)	3.0 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0169
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.5 to -0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 10 mcg qd minus Placebo

50. Secondary Outcome

Title	Patient's Global Rating at Week 24
Description	Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.
Time Frame	Week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	196	202	205
Mean (Standard Error) [Point on scale]	3.3 (0.1)	3.0 (0.1)	2.9 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0180
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.5 to -0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum, visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 10 mcg qd minus Placebo

51. Secondary Outcome

Title	Patient's Global Rating at Week 48
Description	Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven point scale: 1=very much better, 2=much better,3=a little better,4=no change,5=a little worse,6=much worse,7=very much worst.
Time Frame	Week 48 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	196	202	205
Mean (Standard Error) [Point on scale]	3.3 (0.1)	3.1 (0.1)	3.0 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1313
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum,visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	() 95%; -0.4 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments
	Method	Mixed Models Analysis
	Comments	Model included treatment, tiotropium stratum visit and treatment-by-visit interaction as fixed effects, patient as random.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments	Olo 10 mcg qd minus Placebo

52. Secondary Outcome

Title	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Description	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval.
Time Frame	Baseline to end of study at 48 weeks.

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo (Tiotropium)	Placebo (Non-tiotropium)	Olo 5 mcg qd (Tiotropium)	Olo 5 mcg qd (Non-tiotropium)	Olo 10 mcg qd (Tiotropium)	Olo 10 mcg qd(Non-tiotropium)
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler - tiotropium use stratum	Matching Placebo delivered by the Respimat Inhaler - non-tiotropium use stratum.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum
Measure Participants	41	175	39	170	44	173
Mean (95% Confidence Interval) [days]	306.0	259.0	225.0	315.0	219.0	216.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd, Olo 5 mcg qd (Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9853
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.993
	Confidence Interval	(2-Sided) 95%; 0.687 to 1.436
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.187
	Estimation Comments	Comparison of Olo 5 mcg qd to placebo across stratum

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd (Tiotropium), Olo 10 mcg qd(Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2344
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.241
	Confidence Interval	(2-Sided) 95%; 0.873 to 1.763
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.222
	Estimation Comments	Comparison of Olo 10 mcg qd to placebo across stratum

53. Secondary Outcome

Title	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization
Description	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval.
Time Frame	Baseline to end of study at 48 weeks.

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo (Tiotropium)	Placebo (Non-tiotropium)	Olo 5 mcg qd (Tiotropium)	Olo 5 mcg qd (Non-tiotropium)	Olo 10 mcg qd (Tiotropium)	Olo 10 mcg qd(Non-tiotropium)
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler - tiotropium use stratum	Matching Placebo delivered by the Respimat Inhaler - non-tiotropium use stratum.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum
Measure Participants	41	175	39	170	44	173
Mean (95% Confidence Interval) [days]	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd, Olo 5 mcg qd (Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9035
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.050
	Confidence Interval	(2-Sided) 95%; 0.463 to 2.380
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.438
	Estimation Comments	Comparison of Olo 5 mcg qd to placebo across stratum

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd(Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9304
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.958
	Confidence Interval	(2-Sided) 95%; 0.415 to 2.209
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.408
	Estimation Comments	Comparison of Olo 10 mcg qd to placebo across stratum

54. Secondary Outcome

Title	Time to First Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Description	Qualifying events of COPD were specifically pre-defined in the protocol.Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval..
Time Frame	Baseline to end of study at 48 weeks.

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo (Tiotropium)	Placebo (Non-tiotropium)	Olo 5 mcg qd (Tiotropium)	Olo 5 mcg qd (Non-tiotropium)	Olo 10 mcg qd (Tiotropium)	Olo 10 mcg qd(Non-tiotropium)
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler - tiotropium use stratum	Matching Placebo delivered by the Respimat Inhaler - non-tiotropium use stratum.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - tiotropium stratum	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler - non-tiotropium stratum
Measure Participants	41	175	39	170	44	173
Mean (95% Confidence Interval) [days]	NA	362.0	NA	NA	225.0	308.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd, Olo 5 mcg qd (Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6690
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.090
	Confidence Interval	(2-Sided) 95%; 0.717 to 1.657
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.233
	Estimation Comments	Comparison of Olo 5 mcg qd to placebo across stratum

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd, Olo 10 mcg qd (Tiotropium), Olo 10 mcg qd(Non-tiotropium)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1437
	Comments
	Method	Log Rank
	Comments	Model included a stratification factor for tiotropium use stratum and a covariate for treatment group
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.344
	Confidence Interval	(2-Sided) 95%; 0.902 to 2.002
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.273
	Estimation Comments	Comparison of Olo 10 mcg qd to placebo across stratum

55. Secondary Outcome

Title	Number of COPD Exacerbations
Description	Mean number of COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria.
Time Frame	Baseline to end of study at week 48 visit

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	216	209	217
Mean (Standard Error) [COPD exacerbations]	0.4590 (0.0687)	0.5453 (0.0765)	0.5885 (0.0799)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3637
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.1880
	Confidence Interval	(2-Sided) 95%; 0.8188 to 1.7234
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2251
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1853
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.2822
	Confidence Interval	(2-Sided) 95%; 0.8874 to 1.8527
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2403
	Estimation Comments	Olo 10 mcg qd minus Placebo

56. Secondary Outcome

Title	Number of COPD Exacerbations Requiring Hospitalization
Description	Mean number of COPD exacerbations requiring hospitalization per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization.
Time Frame	Baseline to end of study at week 48 visit

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	216	209	217
Mean (Standard Error) [COPD exacerbations]	0.0786 (0.0273)	0.0811 (0.0268)	0.0886 (0.0287)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 5 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9455
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.0314
	Confidence Interval	(2-Sided) 95%; 0.4244 to 2.5063
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4664
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7883
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.1273
	Confidence Interval	(2-Sided) 95%; 0.4696 to 2.7064
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5028
	Estimation Comments	Olo 10 mcg qd minus Placebo

57. Secondary Outcome

Title	Number of Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Description	Mean number of moderate COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids.
Time Frame	Baseline to end of study at 48 weeks.

Outcome Measure Data

Analysis Population Description

Treated set- all patients who received at least one dose of study medication

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	216	209	215
Mean (Standard Error) [COPD exacerbations]	0.3375 (0.0587)	0.4335 (0.0699)	0.4513 (0.0701)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2514
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.2846
	Confidence Interval	(2-Sided) 95%; 0.8370 to 1.9717
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2803
	Estimation Comments	Olo 5 mcg qd minus Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Olo 10 mcg qd
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1807
	Comments
	Method	Negative binomial regression
	Comments	Regression of treatment effect using tiotropium strata as a covariate, a log link function and log(exposure) as offset.
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	1.3373
	Confidence Interval	(2-Sided) 95%; 0.8735 to 2.0474
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2901
	Estimation Comments	Olo 10 mcg qd minus Placebo

58. Secondary Outcome

Title	Changes in Safety Parameters Related to Treatment
Description	Occurence of bronchoconstriction, cardiac disorders and investigations related to treatment. Bronchoconstriction is defined as any of the following events: Drop in trough FEV1 >= 15%, Rescue medication use within 30 min of inhaling randomized treatment on a clinic test day or Cough, wheeze, or dyspnoea AE within 30 min of inhaling randomized treatment on a clinic test day.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Treated set.

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
Measure Participants	216	209	217
Bronchoconstriction	13.9 6.4%	3.3 1.6%	5.5 2.5%
Blood glucose increased	0.0 0%	0.5 0.2%	0.0 0%
Electrocardiogram QT prolonged	0.0 0%	0.5 0.2%	0.0 0%
Ventricular tachycardia	0.0 0%	1.9 0.9%	0.5 0.2%
Ventricular extrasystoles	0.0 0%	1.0 0.5%	1.8 0.8%
Supraventricular extrasystoles	0.0 0%	1.0 0.5%	1.4 0.6%
Atrial fibrillation	0.5 0.2%	0.0 0%	0.0 0%
Atrioventricular block	0.0 0%	0.5 0.2%	0.0 0%
Atrioventricular block first degree	0.0 0%	0.5 0.2%	0.5 0.2%
Atrioventricular block second degree	0.0 0%	0.5 0.2%	0.0 0%
Bundle branch block left	0.0 0%	0.5 0.2%	0.0 0%
Palpitations	0.0 0%	0.0 0%	0.5 0.2%
Sinus bradycardia	0.0 0%	0.5 0.2%	0.0 0%
Sinus tachycardia	0.0 0%	0.5 0.2%	0.0 0%

59. Secondary Outcome

Title	Change From Baseline in Potassium
Description	Laboratory testing: Average change from baseline of potassium measured. The laboratory tests at Day 1 were considered the baseline measurements.
Time Frame	Day 1 and at 12, 24 and 48 weeks

Outcome Measure Data

Analysis Population Description

Treated set.

Arm/Group Title	Placebo	Olo 5 mcg qd	Olo 10 mcg qd
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.	Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olodaterol 10 mcg qd (morning delivered by the Respimat Inhaler.
Measure Participants	207	204	207
Mean (Standard Deviation) [mmol/L]	-0.0 (0.4)	-0.0 (0.4)	0.0 (0.3)

Adverse Events

Time Frame	48 weeks
Arm/Group Title	Placebo		Olo 5 mcg		Olo 10 mcg
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler.		Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.		Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.
All Cause Mortality
	Placebo		Olo 5 mcg		Olo 10 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Olo 5 mcg		Olo 10 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/216 (14.8%)		32/209 (15.3%)		37/217 (17.1%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Cardiac disorders
Acute myocardial infarction	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Atrial fibrillation	1/216 (0.5%)		1/209 (0.5%)		0/217 (0%)
Atrial flutter	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Bradycardia	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Cardiac failure congestive	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Coronary artery disease	1/216 (0.5%)		2/209 (1%)		1/217 (0.5%)
Coronary artery occlusion	1/216 (0.5%)		1/209 (0.5%)		0/217 (0%)
Coronary artery stenosis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Left ventricular dysfunction	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Myocardial infarction	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Ventricular tachycardia	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Eye disorders
Lens dislocation	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Retinal detachment	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Gastrointestinal disorders
Abdominal pain	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Colitis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Diarrhoea	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Gastric polyps	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Gastric ulcer haemorrhage	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Hiatus hernia	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Inguinal hernia	1/216 (0.5%)		1/209 (0.5%)		0/217 (0%)
Intestinal perforation	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Lower gastrointestinal haemorrhage	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Oesophageal rupture	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
General disorders
Chest discomfort	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Chest pain	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Pyrexia	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Sudden cardiac death	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Hepatobiliary disorders
Cholecystitis	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Cholecystitis acute	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Immune system disorders
Contrast media allergy	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Infections and infestations
Helicobacter gastritis	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Infective exacerbation of chronic obstructive airways disease	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Lung infection	1/216 (0.5%)		0/209 (0%)		2/217 (0.9%)
Oesophageal candidiasis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Pneumonia	4/216 (1.9%)		3/209 (1.4%)		5/217 (2.3%)
Pneumonia legionella	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Pneumonia staphylococcal	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Staphylococcal sepsis	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Injury, poisoning and procedural complications
Fall	0/216 (0%)		1/209 (0.5%)		1/217 (0.5%)
Femoral neck fracture	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Hip fracture	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Injury	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Overdose	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Pelvic fracture	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Rib fracture	0/216 (0%)		1/209 (0.5%)		1/217 (0.5%)
Road traffic accident	1/216 (0.5%)		1/209 (0.5%)		1/217 (0.5%)
Spinal compression fracture	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Subdural haemorrhage	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Metabolism and nutrition disorders
Dehydration	0/216 (0%)		2/209 (1%)		0/217 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/216 (0%)		0/209 (0%)		2/217 (0.9%)
Intervertebral disc degeneration	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Intervertebral disc protrusion	0/216 (0%)		1/209 (0.5%)		1/217 (0.5%)
Osteoporosis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Spinal column stenosis	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Spinal osteoarthritis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/216 (0.5%)		1/209 (0.5%)		0/217 (0%)
Bladder cancer	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Hypopharyngeal cancer	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Keratoacanthoma	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Lymphoma	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Small cell lung cancer stage unspecified	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Nervous system disorders
Carotid artery disease	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Cerebrovascular accident	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Subarachnoid haemorrhage	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Transient ischaemic attack	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
VIth nerve paralysis	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Prostatomegaly	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/216 (0%)		1/209 (0.5%)		1/217 (0.5%)
Chronic obstructive pulmonary disease	12/216 (5.6%)		7/209 (3.3%)		12/217 (5.5%)
Dyspnoea	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Haemoptysis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Hydropneumothorax	0/216 (0%)		1/209 (0.5%)		0/217 (0%)
Hypercapnia	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Nasal septum deviation	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Pneumothorax	2/216 (0.9%)		2/209 (1%)		1/217 (0.5%)
Respiratory acidosis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Respiratory failure	1/216 (0.5%)		0/209 (0%)		3/217 (1.4%)
Vascular disorders
Aortic aneurysm	0/216 (0%)		3/209 (1.4%)		0/217 (0%)
Deep vein thrombosis	0/216 (0%)		0/209 (0%)		1/217 (0.5%)
Hypotension	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Peripheral vascular disorder	1/216 (0.5%)		0/209 (0%)		0/217 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Olo 5 mcg		Olo 10 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/216 (34.7%)		71/209 (34%)		81/217 (37.3%)
Infections and infestations
Nasopharyngitis	18/216 (8.3%)		19/209 (9.1%)		25/217 (11.5%)
Upper respiratory tract infection	17/216 (7.9%)		20/209 (9.6%)		22/217 (10.1%)
Nervous system disorders
Headache	11/216 (5.1%)		7/209 (3.3%)		4/217 (1.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	43/216 (19.9%)		39/209 (18.7%)		47/217 (21.7%)

Limitations/Caveats

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

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication