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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01431287

Enrollment

2539

Registered

2011-09-09

Start date

2011-09-30

Completion date

2013-11-30

Last updated

2015-07-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Brief summary

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

Interventions

DRUGtiotropium + olodaterol

fixed dose combination

DRUGtiotropium

low dose or high dose

DRUGolodaterol

one dose only

DEVICERespimat

Respimat inhaler

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Diagnosis of chronic obstructive pulmonary disease. 2. Relatively stable airway obstruction with post FEV1\< 80% predicted normal and post FEV1/FVC \<70%. 3. Male or female patients, 40 years of age or older. 4. Smoking history of more than 10 pack years.

Exclusion criteria

1. Significant disease other than COPD 2. Clinically relevant abnormal lab values. 3. History of asthma. 4. Diagnosis of thyrotoxicosis 5. Diagnosis of paroxysmal tachycardia 6. History of myocardial infarction within 1 year of screening visit 7. Unstable or life-threatening cardiac arrhythmia. 8. Hospitalization for heart failure within the past year. 9. Known active tuberculosis. 10. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years 11. History of life-threatening pulmonary obstruction. 12. History of cystic fibrosis. 13. Clinically evident bronchiectasis. 14. History of significant alcohol or drug abuse. 15. Thoracotomy with pulmonary resection 16. Oral ß-adrenergics. 17. Oral corticosteroid medication at unstable doses 18. Regular use of daytime oxygen therapy for more than one hour per day 19. Pulmonary rehabilitation program in the six weeks prior to the screening visit 20. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit 21. Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA 22. Pregnant or nursing women. 23. Women of childbearing potential not using a highly effective method of birth control 24. Patients who are unable to comply with pulmonary medication restrictions

Design outcomes

Primary

Measure	Time frame	Description
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.
Trough FEV1 Response on Day 170	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	Day 169	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Secondary

Measure	Time frame	Description
FEV1 AUC(0-3h) Response on Day 365	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FEV1 Response on Day 15	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FEV1 Response on Day 43	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FEV1 Response on Day 85	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 85	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FEV1 Response on Day 169	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 169	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FEV1 Response on Day 365	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FVC Response on Day 15	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.
Trough FVC Response on Day 43	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 169	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) is the key secondary endpoint. The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Trough FVC Response on Day 170	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23h and at 23h 50 min after inhalation of study medication on day 170	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day. Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
Trough FVC Response on Day 365	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.
FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169	FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169	FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169	FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169	FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 85	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 365	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 43	Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 85	Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Day 365	Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.
Trough FVC Response on Day 85	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements. Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.
FEV1 AUC(0-3h) Response on Day 1	1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.
FEV1 AUC(0-3h) Response on Day 85	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1. The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Countries

Austria, Belgium, Brazil, Canada, China, Colombia, Croatia, Germany, Hungary, India, Ireland, Japan, Norway, Romania, Russia, Serbia, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States

Participant flow

Pre-assignment details

This trial was one of 2 confirmatory Phase III 52-week, multi-centre, multi-national, randomised, double-blind, parallel group studies to evaluate the long-term efficacy and safety of once daily treatment with orally inhaled Tio+Olo FDC (2.5/5μg; 5/5μg) compared with the individual components (2.5μg; 5μg Tiotropium, 5μg Olodaterol) in COPD patients

Participants by arm

Arm	Count
Olodaterol (5 μg) Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	510
Tiotropium (2.5 μg) Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	507
Tiotropium (5 μg) Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	506
Tio+Olo FDC (2.5/5 μg) Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	508
Tio+Olo FDC (5/5 μg) Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	507
Total	2,538

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Adverse Event	59	57	53	33	41
Overall Study	Consent withdrawn not due to AE	29	30	34	19	29
Overall Study	Lost to Follow-up	0	3	2	3	1
Overall Study	Non compliant with protocol	6	6	5	6	5
Overall Study	not stated above	4	2	2	2	1
Overall Study	not treated	0	0	1	0	0

Baseline characteristics

Characteristic	Olodaterol (5 μg)	Tiotropium (2.5 μg)	Tiotropium (5 μg)	Tio+Olo FDC (2.5/5 μg)	Tio+Olo FDC (5/5 μg)	Total
Age, Continuous	64.7 years STANDARD_DEVIATION 8.3	63.9 years STANDARD_DEVIATION 8.7	63.5 years STANDARD_DEVIATION 8.7	64.1 years STANDARD_DEVIATION 7.6	62.7 years STANDARD_DEVIATION 8.4	63.8 years STANDARD_DEVIATION 8.4
Sex: Female, Male Female	132 Participants	146 Participants	134 Participants	140 Participants	158 Participants	710 Participants
Sex: Female, Male Male	378 Participants	361 Participants	372 Participants	368 Participants	349 Participants	1828 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	246 / 510	228 / 507	216 / 506	223 / 508	214 / 507
serious Total, serious adverse events	106 / 510	90 / 507	93 / 506	87 / 508	82 / 507

Outcome results

Primary

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

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.136 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.125 Litres	Standard Error 0.009
Tiotropium (5 μg)	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.165 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.256 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.268 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.108, 0.157]Mixed Models Analysis

p-value: <0.000195% CI: [0.078, 0.127]Mixed Models Analysis

p-value: <0.000195% CI: [0.096, 0.145]Mixed Models Analysis

p-value: <0.000195% CI: [0.106, 0.155]Mixed Models Analysis

p-value: <0.000195% CI: [0.066, 0.115]Mixed Models Analysis

p-value: 0.339495% CI: [-0.013, 0.036]Mixed Models Analysis

p-value: <0.000195% CI: [0.118, 0.167]Mixed Models Analysis

p-value: 0.017395% CI: [0.005, 0.054]Mixed Models Analysis

p-value: 0.42195% CI: [-0.035, 0.014]Mixed Models Analysis

p-value: 0.001495% CI: [0.015, 0.064]Mixed Models Analysis

Primary

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

The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Time frame: Day 169

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	38.366 points on a scale	Standard Error 0.396
Tiotropium (2.5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	37.792 points on a scale	Standard Error 0.39
Tiotropium (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	37.907 points on a scale	Standard Error 0.393
Tio+Olo FDC (2.5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	37.335 points on a scale	Standard Error 0.385
Tio+Olo FDC (5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	36.674 points on a scale	Standard Error 0.386

p-value: 0.002295% CI: [-2.778, -0.608]Mixed Models Analysis

p-value: 0.025295% CI: [-2.313, -0.153]Mixed Models Analysis

p-value: 0.06295% CI: [-2.113, 0.052]Mixed Models Analysis

p-value: 0.405195% CI: [-1.531, 0.618]Mixed Models Analysis

p-value: 0.298895% CI: [-1.649, 0.507]Mixed Models Analysis

p-value: 0.224995% CI: [-1.731, 0.407]Mixed Models Analysis

p-value: 0.041895% CI: [-2.195, -0.042]Mixed Models Analysis

p-value: 0.409795% CI: [-1.552, 0.633]Mixed Models Analysis

p-value: 0.301395% CI: [-1.664, 0.515]Mixed Models Analysis

p-value: 0.835595% CI: [-0.97, 1.2]Mixed Models Analysis

Primary

Trough FEV1 Response on Day 170

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

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 170	0.057 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 170	0.062 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 170	0.096 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 170	0.125 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 170	0.145 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.063, 0.113]Mixed Models Analysis

p-value: 0.000195% CI: [0.024, 0.075]Mixed Models Analysis

p-value: <0.000195% CI: [0.042, 0.092]Mixed Models Analysis

p-value: <0.000195% CI: [0.037, 0.087]Mixed Models Analysis

p-value: 0.023195% CI: [0.004, 0.054]Mixed Models Analysis

p-value: 0.107395% CI: [-0.004, 0.046]Mixed Models Analysis

p-value: <0.000195% CI: [0.058, 0.108]Mixed Models Analysis

p-value: 0.002995% CI: [0.013, 0.063]Mixed Models Analysis

p-value: 0.693995% CI: [-0.02, 0.03]Mixed Models Analysis

p-value: 0.009795% CI: [0.008, 0.058]Mixed Models Analysis

Secondary

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

FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.131 Litres	Standard Error 0.015
Tiotropium (2.5 μg)	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.109 Litres	Standard Error 0.016
Tiotropium (5 μg)	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.127 Litres	Standard Error 0.017
Tio+Olo FDC (2.5/5 μg)	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.202 Litres	Standard Error 0.016
Tio+Olo FDC (5/5 μg)	FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.250 Litres	Standard Error 0.016

p-value: <0.000195% CI: [0.074, 0.162]ANCOVA

p-value: <0.000195% CI: [0.077, 0.169]ANCOVA

p-value: 0.001295% CI: [0.028, 0.114]ANCOVA

p-value: <0.000195% CI: [0.05, 0.137]ANCOVA

p-value: 0.00195% CI: [0.031, 0.121]ANCOVA

p-value: 0.038495% CI: [0.003, 0.092]ANCOVA

p-value: <0.000195% CI: [0.097, 0.185]ANCOVA

p-value: 0.842895% CI: [-0.049, 0.04]ANCOVA

p-value: 0.304895% CI: [-0.065, 0.02]ANCOVA

p-value: 0.431195% CI: [-0.027, 0.063]ANCOVA

Secondary

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

FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169

Population: 12-hr PFT set

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.108 Litres	Standard Error 0.014
Tiotropium (2.5 μg)	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.083 Litres	Standard Error 0.015
Tiotropium (5 μg)	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.100 Litres	Standard Error 0.016
Tio+Olo FDC (2.5/5 μg)	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.159 Litres	Standard Error 0.015
Tio+Olo FDC (5/5 μg)	FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.206 Litres	Standard Error 0.015

p-value: <0.000195% CI: [0.057, 0.139]ANCOVA

p-value: <0.000195% CI: [0.063, 0.149]ANCOVA

p-value: 0.013695% CI: [0.01, 0.091]ANCOVA

p-value: 0.000395% CI: [0.035, 0.116]ANCOVA

p-value: 0.006595% CI: [0.016, 0.101]ANCOVA

p-value: 0.027795% CI: [0.005, 0.089]ANCOVA

p-value: <0.000195% CI: [0.081, 0.164]ANCOVA

p-value: 0.711695% CI: [-0.049, 0.034]ANCOVA

p-value: 0.233295% CI: [-0.065, 0.016]ANCOVA

p-value: 0.437495% CI: [-0.025, 0.059]ANCOVA

Secondary

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

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FEV1 AUC(0-3h) Response on Day 1	0.196 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	FEV1 AUC(0-3h) Response on Day 1	0.135 Litres	Standard Error 0.009
Tiotropium (5 μg)	FEV1 AUC(0-3h) Response on Day 1	0.164 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	FEV1 AUC(0-3h) Response on Day 1	0.228 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	FEV1 AUC(0-3h) Response on Day 1	0.229 Litres	Standard Error 0.009

p-value: 0.009595% CI: [0.008, 0.058]Mixed Models Analysis

p-value: <0.000195% CI: [0.04, 0.09]Mixed Models Analysis

p-value: 0.011295% CI: [0.007, 0.058]Mixed Models Analysis

p-value: <0.000195% CI: [0.068, 0.119]Mixed Models Analysis

p-value: <0.000195% CI: [0.039, 0.09]Mixed Models Analysis

p-value: 0.951495% CI: [-0.024, 0.026]Mixed Models Analysis

p-value: <0.000195% CI: [0.069, 0.119]Mixed Models Analysis

p-value: 0.013195% CI: [-0.057, -0.007]Mixed Models Analysis

p-value: <0.000195% CI: [-0.086, -0.036]Mixed Models Analysis

p-value: 0.024395% CI: [0.004, 0.054]Mixed Models Analysis

Secondary

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

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FEV1 AUC(0-3h) Response on Day 365	0.105 Litres	Standard Error 0.01
Tiotropium (2.5 μg)	FEV1 AUC(0-3h) Response on Day 365	0.105 Litres	Standard Error 0.01
Tiotropium (5 μg)	FEV1 AUC(0-3h) Response on Day 365	0.124 Litres	Standard Error 0.01
Tio+Olo FDC (2.5/5 μg)	FEV1 AUC(0-3h) Response on Day 365	0.223 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	FEV1 AUC(0-3h) Response on Day 365	0.237 Litres	Standard Error 0.01

p-value: <0.000195% CI: [0.105, 0.158]Mixed Models Analysis

p-value: <0.000195% CI: [0.086, 0.139]Mixed Models Analysis

p-value: <0.000195% CI: [0.092, 0.144]Mixed Models Analysis

p-value: <0.000195% CI: [0.072, 0.125]Mixed Models Analysis

p-value: 0.300895% CI: [-0.012, 0.04]Mixed Models Analysis

p-value: <0.000195% CI: [0.105, 0.158]Mixed Models Analysis

p-value: 0.148495% CI: [-0.007, 0.046]Mixed Models Analysis

p-value: 0.998195% CI: [-0.026, 0.027]Mixed Models Analysis

p-value: 0.14895% CI: [-0.007, 0.046]Mixed Models Analysis

Secondary

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

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FEV1 AUC(0-3h) Response on Day 85	0.153 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	FEV1 AUC(0-3h) Response on Day 85	0.165 Litres	Standard Error 0.009
Tiotropium (5 μg)	FEV1 AUC(0-3h) Response on Day 85	0.187 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	FEV1 AUC(0-3h) Response on Day 85	0.272 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	FEV1 AUC(0-3h) Response on Day 85	0.297 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.119, 0.17]Mixed Models Analysis

p-value: <0.000195% CI: [0.085, 0.136]Mixed Models Analysis

p-value: <0.000195% CI: [0.094, 0.144]Mixed Models Analysis

p-value: <0.000195% CI: [0.081, 0.132]Mixed Models Analysis

p-value: <0.000195% CI: [0.059, 0.11]Mixed Models Analysis

p-value: 0.04795% CI: [0, 0.051]Mixed Models Analysis

p-value: <0.000195% CI: [0.107, 0.158]Mixed Models Analysis

p-value: 0.008395% CI: [0.009, 0.06]Mixed Models Analysis

p-value: 0.332995% CI: [-0.013, 0.038]Mixed Models Analysis

p-value: 0.095895% CI: [-0.004, 0.047]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment

Population: FAS (day 1). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Arm	Measure	Value (MEDIAN)	Dispersion
Olodaterol (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.341 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.264 Litres	Standard Error 0.018
Tiotropium (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.298 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.411 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.397 Litres	Standard Error 0.018

p-value: 0.024195% CI: [0.007, 0.105]Mixed Models Analysis

p-value: <0.000195% CI: [0.051, 0.148]Mixed Models Analysis

p-value: 0.004995% CI: [0.021, 0.119]Mixed Models Analysis

p-value: <0.000195% CI: [0.098, 0.196]Mixed Models Analysis

p-value: <0.000195% CI: [0.064, 0.162]Mixed Models Analysis

p-value: 0.583195% CI: [-0.063, 0.035]Mixed Models Analysis

p-value: <0.000195% CI: [0.084, 0.182]Mixed Models Analysis

p-value: 0.082295% CI: [-0.092, 0.006]Mixed Models Analysis

p-value: 0.00295% CI: [-0.126, -0.028]Mixed Models Analysis

p-value: 0.177495% CI: [-0.015, 0.083]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169

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

Arm	Measure	Value (MEDIAN)	Dispersion
Olodaterol (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.231 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.247 Litres	Standard Error 0.018
Tiotropium (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.283 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.439 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.429 Litres	Standard Error 0.018

p-value: <0.000195% CI: [0.148, 0.248]Mixed Models Analysis

p-value: <0.000195% CI: [0.096, 0.197]Mixed Models Analysis

p-value: <0.000195% CI: [0.158, 0.258]Mixed Models Analysis

p-value: <0.000195% CI: [0.143, 0.242]Mixed Models Analysis

p-value: <0.000195% CI: [0.106, 0.206]Mixed Models Analysis

p-value: 0.69895% CI: [-0.06, 0.04]Mixed Models Analysis

p-value: <0.000195% CI: [0.132, 0.233]Mixed Models Analysis

p-value: 0.044295% CI: [0.001, 0.102]Mixed Models Analysis

p-value: 0.551495% CI: [-0.035, 0.065]Mixed Models Analysis

p-value: 0.156995% CI: [-0.014, 0.086]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365

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

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365

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

Arm	Measure	Value (MEDIAN)	Dispersion
Olodaterol (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.180 Litres	Standard Error 0.019
Tiotropium (2.5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.216 Litres	Standard Error 0.018
Tiotropium (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.198 Litres	Standard Error 0.019
Tio+Olo FDC (2.5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.397 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.381 Litres	Standard Error 0.019

p-value: <0.000195% CI: [0.15, 0.253]Mixed Models Analysis

p-value: <0.000195% CI: [0.132, 0.234]Mixed Models Analysis

p-value: <0.000195% CI: [0.167, 0.269]Mixed Models Analysis

p-value: <0.000195% CI: [0.13, 0.232]Mixed Models Analysis

p-value: <0.000195% CI: [0.148, 0.25]Mixed Models Analysis

p-value: 0.537395% CI: [-0.067, 0.035]Mixed Models Analysis

p-value: <0.000195% CI: [0.114, 0.216]Mixed Models Analysis

p-value: 0.476395% CI: [-0.033, 0.07]Mixed Models Analysis

p-value: 0.161395% CI: [-0.015, 0.088]Mixed Models Analysis

p-value: 0.490895% CI: [-0.069, 0.033]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85

Time frame: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85

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

Arm	Measure	Value (MEDIAN)	Dispersion
Olodaterol (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.250 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.306 Litres	Standard Error 0.018
Tiotropium (5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.326 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.460 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.469 Litres	Standard Error 0.018

p-value: <0.000195% CI: [0.169, 0.268]Mixed Models Analysis

p-value: <0.000195% CI: [0.094, 0.193]Mixed Models Analysis

p-value: <0.000195% CI: [0.16, 0.258]Mixed Models Analysis

p-value: <0.000195% CI: [0.104, 0.203]Mixed Models Analysis

p-value: <0.000195% CI: [0.084, 0.183]Mixed Models Analysis

p-value: 0.697495% CI: [-0.04, 0.059]Mixed Models Analysis

p-value: <0.000195% CI: [0.114, 0.213]Mixed Models Analysis

p-value: 0.002795% CI: [0.026, 0.125]Mixed Models Analysis

p-value: 0.026995% CI: [0.006, 0.105]Mixed Models Analysis

p-value: 0.434395% CI: [-0.03, 0.069]Mixed Models Analysis

Secondary

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

FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Population: 12-hr PFT set

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.227 Litres	Standard Error 0.029
Tiotropium (2.5 μg)	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.180 Litres	Standard Error 0.03
Tiotropium (5 μg)	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.248 Litres	Standard Error 0.032
Tio+Olo FDC (2.5/5 μg)	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.356 Litres	Standard Error 0.03
Tio+Olo FDC (5/5 μg)	FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.388 Litres	Standard Error 0.031

p-value: 0.000295% CI: [0.077, 0.244]ANCOVA

p-value: 0.001795% CI: [0.053, 0.228]ANCOVA

p-value: 0.002295% CI: [0.046, 0.21]ANCOVA

p-value: <0.000195% CI: [0.093, 0.259]ANCOVA

p-value: 0.014195% CI: [0.022, 0.194]ANCOVA

p-value: 0.458195% CI: [-0.053, 0.118]ANCOVA

p-value: <0.000195% CI: [0.124, 0.293]ANCOVA

p-value: 0.633595% CI: [-0.064, 0.105]ANCOVA

p-value: 0.25395% CI: [-0.129, 0.034]ANCOVA

p-value: 0.118895% CI: [-0.017, 0.153]ANCOVA

Secondary

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

FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Population: 12-hr PFT set

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.192 Litres	Standard Error 0.028
Tiotropium (2.5 μg)	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.141 Litres	Standard Error 0.028
Tiotropium (5 μg)	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.203 Litres	Standard Error 0.03
Tio+Olo FDC (2.5/5 μg)	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.297 Litres	Standard Error 0.029
Tio+Olo FDC (5/5 μg)	FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.329 Litres	Standard Error 0.03

p-value: 0.000895% CI: [0.057, 0.217]ANCOVA

p-value: 0.003295% CI: [0.042, 0.209]ANCOVA

p-value: 0.008595% CI: [0.027, 0.183]ANCOVA

p-value: 0.000195% CI: [0.077, 0.235]ANCOVA

p-value: 0.025595% CI: [0.011, 0.176]ANCOVA

p-value: 0.439395% CI: [-0.049, 0.113]ANCOVA

p-value: <0.000195% CI: [0.108, 0.269]ANCOVA

p-value: 0.778495% CI: [-0.069, 0.092]ANCOVA

p-value: 0.196595% CI: [-0.129, 0.026]ANCOVA

p-value: 0.131595% CI: [-0.019, 0.144]ANCOVA

Secondary

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

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

Time frame: Day 169

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.564 points on a scale	Standard Error 0.096
Tiotropium (2.5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.690 points on a scale	Standard Error 0.095
Tiotropium (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.627 points on a scale	Standard Error 0.096
Tio+Olo FDC (2.5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.980 points on a scale	Standard Error 0.095
Tio+Olo FDC (5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.983 points on a scale	Standard Error 0.095

p-value: 0.001995% CI: [0.155, 0.684]Mixed Models Analysis

p-value: 0.008295% CI: [0.092, 0.619]Mixed Models Analysis

p-value: 0.00295% CI: [0.152, 0.681]Mixed Models Analysis

p-value: 0.030795% CI: [0.027, 0.554]Mixed Models Analysis

p-value: 0.008895% CI: [0.089, 0.616]Mixed Models Analysis

p-value: 0.980195% CI: [-0.259, 0.266]Mixed Models Analysis

p-value: 0.028995% CI: [0.03, 0.557]Mixed Models Analysis

p-value: 0.638295% CI: [-0.202, 0.33]Mixed Models Analysis

p-value: 0.352595% CI: [-0.14, 0.391]Mixed Models Analysis

p-value: 0.645795% CI: [-0.327, 0.203]Mixed Models Analysis

Secondary

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

Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Time frame: Day 365

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.411 points on a scale	Standard Error 0.101
Tiotropium (2.5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.450 points on a scale	Standard Error 0.1
Tiotropium (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.736 points on a scale	Standard Error 0.101
Tio+Olo FDC (2.5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.782 points on a scale	Standard Error 0.099
Tio+Olo FDC (5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	2.058 points on a scale	Standard Error 0.099

p-value: <0.000195% CI: [0.37, 0.925]Mixed Models Analysis

p-value: 0.022695% CI: [0.045, 0.6]Mixed Models Analysis

p-value: 0.008995% CI: [0.093, 0.649]Mixed Models Analysis

p-value: 0.018695% CI: [0.056, 0.609]Mixed Models Analysis

p-value: 0.744195% CI: [-0.231, 0.324]Mixed Models Analysis

p-value: 0.049295% CI: [0.001, 0.551]Mixed Models Analysis

p-value: <0.000195% CI: [0.332, 0.884]Mixed Models Analysis

p-value: 0.02395% CI: [0.045, 0.605]Mixed Models Analysis

p-value: 0.785595% CI: [-0.24, 0.317]Mixed Models Analysis

p-value: 0.044295% CI: [0.007, 0.564]Mixed Models Analysis

Secondary

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

Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Time frame: Day 43

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.453 points on a scale	Standard Error 0.096
Tiotropium (2.5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.430 points on a scale	Standard Error 0.097
Tiotropium (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.408 points on a scale	Standard Error 0.097
Tio+Olo FDC (2.5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.876 points on a scale	Standard Error 0.096
Tio+Olo FDC (5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	2.048 points on a scale	Standard Error 0.096

p-value: <0.000195% CI: [0.329, 0.862]Mixed Models Analysis

p-value: <0.000195% CI: [0.373, 0.907]Mixed Models Analysis

p-value: 0.001995% CI: [0.156, 0.69]Mixed Models Analysis

p-value: 0.001195% CI: [0.179, 0.712]Mixed Models Analysis

p-value: 0.000695% CI: [0.201, 0.735]Mixed Models Analysis

p-value: 0.204595% CI: [-0.094, 0.438]Mixed Models Analysis

p-value: <0.000195% CI: [0.351, 0.885]Mixed Models Analysis

p-value: 0.743295% CI: [-0.313, 0.223]Mixed Models Analysis

p-value: 0.868795% CI: [-0.29, 0.245]Mixed Models Analysis

p-value: 0.870995% CI: [-0.29, 0.246]Mixed Models Analysis

Secondary

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

Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Time frame: Day 85

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.506 points on a scale	Standard Error 0.097
Tiotropium (2.5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.698 points on a scale	Standard Error 0.097
Tiotropium (5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.702 points on a scale	Standard Error 0.097
Tio+Olo FDC (2.5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.925 points on a scale	Standard Error 0.096
Tio+Olo FDC (5/5 μg)	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	2.136 points on a scale	Standard Error 0.096

p-value: <0.000195% CI: [0.362, 0.898]Mixed Models Analysis

p-value: 0.001595% CI: [0.166, 0.703]Mixed Models Analysis

p-value: 0.002295% CI: [0.151, 0.687]Mixed Models Analysis

p-value: 0.096695% CI: [-0.041, 0.495]Mixed Models Analysis

p-value: 0.102995% CI: [-0.045, 0.492]Mixed Models Analysis

p-value: 0.12295% CI: [-0.056, 0.478]Mixed Models Analysis

p-value: 0.001495% CI: [0.17, 0.707]Mixed Models Analysis

p-value: 0.154295% CI: [-0.074, 0.465]Mixed Models Analysis

p-value: 0.162695% CI: [-0.077, 0.461]Mixed Models Analysis

p-value: 0.976595% CI: [-0.265, 0.274]Mixed Models Analysis

Secondary

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

Time frame: Day 365

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	38.989 points on a scale	Standard Error 0.414
Tiotropium (2.5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.609 points on a scale	Standard Error 0.409
Tiotropium (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.581 points on a scale	Standard Error 0.411
Tio+Olo FDC (2.5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.553 points on a scale	Standard Error 0.403
Tio+Olo FDC (5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.138 points on a scale	Standard Error 0.404

p-value: 0.001495% CI: [-2.985, -0.718]Mixed Models Analysis

p-value: 0.441395% CI: [-1.573, 0.686]Mixed Models Analysis

p-value: 0.012995% CI: [-2.569, -0.304]Mixed Models Analysis

p-value: 0.922295% CI: [-1.182, 1.07]Mixed Models Analysis

p-value: 0.960295% CI: [-1.157, 1.1]Mixed Models Analysis

p-value: 0.466995% CI: [-1.533, 0.703]Mixed Models Analysis

p-value: 0.412695% CI: [-1.598, 0.656]Mixed Models Analysis

p-value: 0.015895% CI: [-2.551, -0.265]Mixed Models Analysis

p-value: 0.017795% CI: [-2.521, -0.24]Mixed Models Analysis

p-value: 0.962495% CI: [-1.164, 1.109]Mixed Models Analysis

Secondary

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

Time frame: Day 85

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	38.832 points on a scale	Standard Error 0.398
Tiotropium (2.5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.821 points on a scale	Standard Error 0.397
Tiotropium (5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.822 points on a scale	Standard Error 0.399
Tio+Olo FDC (2.5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	37.304 points on a scale	Standard Error 0.392
Tio+Olo FDC (5/5 μg)	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	36.691 points on a scale	Standard Error 0.394

p-value: 0.000195% CI: [-3.239, -1.043]Mixed Models Analysis

p-value: 0.043595% CI: [-2.23, -0.033]Mixed Models Analysis

p-value: 0.006395% CI: [-2.623, -0.432]Mixed Models Analysis

p-value: 0.354595% CI: [-1.611, 0.577]Mixed Models Analysis

p-value: 0.354295% CI: [-1.614, 0.578]Mixed Models Analysis

p-value: 0.269795% CI: [-1.702, 0.476]Mixed Models Analysis

p-value: 0.043495% CI: [-2.227, -0.033]Mixed Models Analysis

p-value: 0.073295% CI: [-2.114, 0.095]Mixed Models Analysis

p-value: 0.072495% CI: [-2.114, 0.092]Mixed Models Analysis

p-value: 0.998395% CI: [-1.102, 1.104]Mixed Models Analysis

Secondary

Trough FEV1 Response on Day 15

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

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 15	0.083 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 15	0.085 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 15	0.112 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 15	0.147 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 15	0.148 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.04, 0.09]Mixed Models Analysis

p-value: 0.00595% CI: [0.011, 0.061]Mixed Models Analysis

p-value: <0.000195% CI: [0.039, 0.089]Mixed Models Analysis

p-value: <0.000195% CI: [0.037, 0.088]Mixed Models Analysis

p-value: 0.005795% CI: [0.01, 0.061]Mixed Models Analysis

p-value: 0.963395% CI: [-0.025, 0.026]Mixed Models Analysis

p-value: <0.000195% CI: [0.038, 0.088]Mixed Models Analysis

p-value: 0.02595% CI: [0.004, 0.054]Mixed Models Analysis

p-value: 0.894995% CI: [-0.023, 0.027]Mixed Models Analysis

p-value: 0.035195% CI: [0.002, 0.052]Mixed Models Analysis

Secondary

Trough FEV1 Response on Day 169

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 169

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 169	0.034 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 169	0.041 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 169	0.068 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 169	0.111 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 169	0.119 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.059, 0.111]Mixed Models Analysis

p-value: 0.000195% CI: [0.025, 0.076]Mixed Models Analysis

p-value: <0.000195% CI: [0.051, 0.102]Mixed Models Analysis

p-value: <0.000195% CI: [0.044, 0.095]Mixed Models Analysis

p-value: 0.001395% CI: [0.016, 0.068]Mixed Models Analysis

p-value: 0.527495% CI: [-0.017, 0.034]Mixed Models Analysis

p-value: <0.000195% CI: [0.052, 0.103]Mixed Models Analysis

p-value: 0.008395% CI: [0.009, 0.06]Mixed Models Analysis

p-value: 0.574495% CI: [-0.018, 0.033]Mixed Models Analysis

p-value: 0.038195% CI: [0.001, 0.053]Mixed Models Analysis

Secondary

Trough FEV1 Response on Day 365

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 365	0.011 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 365	0.022 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 365	0.040 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 365	0.077 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 365	0.093 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.055, 0.108]Mixed Models Analysis

p-value: <0.000195% CI: [0.027, 0.079]Mixed Models Analysis

p-value: <0.000195% CI: [0.039, 0.091]Mixed Models Analysis

p-value: <0.000195% CI: [0.029, 0.081]Mixed Models Analysis

p-value: 0.005295% CI: [0.011, 0.063]Mixed Models Analysis

p-value: 0.227395% CI: [-0.01, 0.042]Mixed Models Analysis

p-value: <0.000195% CI: [0.045, 0.097]Mixed Models Analysis

p-value: 0.03395% CI: [0.002, 0.055]Mixed Models Analysis

p-value: 0.432795% CI: [-0.016, 0.037]Mixed Models Analysis

p-value: 0.176495% CI: [-0.008, 0.044]Mixed Models Analysis

Secondary

Trough FEV1 Response on Day 43

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 43	0.070 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 43	0.085 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 43	0.103 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 43	0.146 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 43	0.150 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.055, 0.105]Mixed Models Analysis

p-value: 0.000295% CI: [0.022, 0.073]Mixed Models Analysis

p-value: <0.000195% CI: [0.051, 0.101]Mixed Models Analysis

p-value: <0.000195% CI: [0.036, 0.086]Mixed Models Analysis

p-value: 0.000795% CI: [0.018, 0.069]Mixed Models Analysis

p-value: 0.775595% CI: [-0.022, 0.029]Mixed Models Analysis

p-value: <0.000195% CI: [0.039, 0.09]Mixed Models Analysis

p-value: 0.011895% CI: [0.007, 0.058]Mixed Models Analysis

p-value: 0.241695% CI: [-0.01, 0.04]Mixed Models Analysis

p-value: 0.179295% CI: [-0.008, 0.043]Mixed Models Analysis

Secondary

Trough FEV1 Response on Day 85

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 85

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FEV1 Response on Day 85	0.047 Litres	Standard Error 0.009
Tiotropium (2.5 μg)	Trough FEV1 Response on Day 85	0.081 Litres	Standard Error 0.009
Tiotropium (5 μg)	Trough FEV1 Response on Day 85	0.088 Litres	Standard Error 0.009
Tio+Olo FDC (2.5/5 μg)	Trough FEV1 Response on Day 85	0.129 Litres	Standard Error 0.009
Tio+Olo FDC (5/5 μg)	Trough FEV1 Response on Day 85	0.147 Litres	Standard Error 0.009

p-value: <0.000195% CI: [0.074, 0.125]Mixed Models Analysis

p-value: <0.000195% CI: [0.033, 0.084]Mixed Models Analysis

p-value: <0.000195% CI: [0.057, 0.107]Mixed Models Analysis

p-value: 0.000295% CI: [0.023, 0.073]Mixed Models Analysis

p-value: 0.001495% CI: [0.016, 0.067]Mixed Models Analysis

p-value: 0.174795% CI: [-0.008, 0.043]Mixed Models Analysis

p-value: <0.000195% CI: [0.04, 0.091]Mixed Models Analysis

p-value: 0.001695% CI: [0.016, 0.066]Mixed Models Analysis

p-value: 0.008195% CI: [0.009, 0.06]Mixed Models Analysis

p-value: 0.61195% CI: [-0.019, 0.032]Mixed Models Analysis

Secondary

Trough FVC Response on Day 15

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

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FVC Response on Day 15	0.163 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Trough FVC Response on Day 15	0.209 Litres	Standard Error 0.018
Tiotropium (5 μg)	Trough FVC Response on Day 15	0.222 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Trough FVC Response on Day 15	0.293 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Trough FVC Response on Day 15	0.285 Litres	Standard Error 0.018

p-value: <0.000195% CI: [0.072, 0.173]Mixed Models Analysis

p-value: 0.015495% CI: [0.012, 0.113]Mixed Models Analysis

p-value: <0.000195% CI: [0.08, 0.181]Mixed Models Analysis

p-value: 0.001295% CI: [0.033, 0.134]Mixed Models Analysis

p-value: 0.006195% CI: [0.02, 0.121]Mixed Models Analysis

p-value: 0.751895% CI: [-0.059, 0.042]Mixed Models Analysis

p-value: 0.003495% CI: [0.025, 0.126]Mixed Models Analysis

p-value: 0.020995% CI: [0.009, 0.11]Mixed Models Analysis

p-value: 0.070895% CI: [-0.004, 0.097]Mixed Models Analysis

p-value: 0.614895% CI: [-0.038, 0.064]Mixed Models Analysis

Secondary

Trough FVC Response on Day 170

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

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23h and at 23h 50 min after inhalation of study medication on day 170

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FVC Response on Day 170	0.116 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Trough FVC Response on Day 170	0.163 Litres	Standard Error 0.018
Tiotropium (5 μg)	Trough FVC Response on Day 170	0.202 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Trough FVC Response on Day 170	0.266 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Trough FVC Response on Day 170	0.274 Litres	Standard Error 0.018

p-value: <0.000195% CI: [0.108, 0.208]Mixed Models Analysis

p-value: 0.004895% CI: [0.022, 0.122]Mixed Models Analysis

p-value: <0.000195% CI: [0.101, 0.2]Mixed Models Analysis

p-value: <0.000195% CI: [0.053, 0.152]Mixed Models Analysis

p-value: 0.011695% CI: [0.014, 0.113]Mixed Models Analysis

p-value: 0.757795% CI: [-0.042, 0.058]Mixed Models Analysis

p-value: <0.000195% CI: [0.061, 0.16]Mixed Models Analysis

p-value: 0.000795% CI: [0.037, 0.136]Mixed Models Analysis

p-value: 0.062195% CI: [-0.002, 0.097]Mixed Models Analysis

p-value: 0.126695% CI: [-0.011, 0.089]Mixed Models Analysis

Secondary

Trough FVC Response on Day 365

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FVC Response on Day 365	0.028 Litres	Standard Error 0.019
Tiotropium (2.5 μg)	Trough FVC Response on Day 365	0.096 Litres	Standard Error 0.019
Tiotropium (5 μg)	Trough FVC Response on Day 365	0.097 Litres	Standard Error 0.019
Tio+Olo FDC (2.5/5 μg)	Trough FVC Response on Day 365	0.198 Litres	Standard Error 0.019
Tio+Olo FDC (5/5 μg)	Trough FVC Response on Day 365	0.184 Litres	Standard Error 0.019

p-value: <0.000195% CI: [0.104, 0.209]Mixed Models Analysis

p-value: 0.001395% CI: [0.034, 0.139]Mixed Models Analysis

p-value: <0.000195% CI: [0.118, 0.223]Mixed Models Analysis

p-value: 0.000195% CI: [0.049, 0.154]Mixed Models Analysis

p-value: 0.000295% CI: [0.048, 0.153]Mixed Models Analysis

p-value: 0.609395% CI: [-0.066, 0.039]Mixed Models Analysis

p-value: 0.001195% CI: [0.035, 0.14]Mixed Models Analysis

p-value: 0.009595% CI: [0.017, 0.123]Mixed Models Analysis

p-value: 0.010895% CI: [0.016, 0.121]Mixed Models Analysis

p-value: 0.962795% CI: [-0.051, 0.054]Mixed Models Analysis

Secondary

Trough FVC Response on Day 43

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FVC Response on Day 43	0.129 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Trough FVC Response on Day 43	0.206 Litres	Standard Error 0.018
Tiotropium (5 μg)	Trough FVC Response on Day 43	0.222 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Trough FVC Response on Day 43	0.281 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Trough FVC Response on Day 43	0.293 Litres	Standard Error 0.018

p-value: <0.000195% CI: [0.114, 0.215]Mixed Models Analysis

p-value: 0.006495% CI: [0.02, 0.122]Mixed Models Analysis

p-value: <0.000195% CI: [0.102, 0.203]Mixed Models Analysis

p-value: 0.003595% CI: [0.025, 0.126]Mixed Models Analysis

p-value: 0.023395% CI: [0.008, 0.109]Mixed Models Analysis

p-value: 0.641395% CI: [-0.039, 0.063]Mixed Models Analysis

p-value: 0.000795% CI: [0.037, 0.138]Mixed Models Analysis

p-value: 0.000395% CI: [0.043, 0.144]Mixed Models Analysis

p-value: 0.00395% CI: [0.026, 0.127]Mixed Models Analysis

p-value: 0.515995% CI: [-0.034, 0.068]Mixed Models Analysis

Secondary

Trough FVC Response on Day 85

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Olodaterol (5 μg)	Trough FVC Response on Day 85	0.063 Litres	Standard Error 0.018
Tiotropium (2.5 μg)	Trough FVC Response on Day 85	0.178 Litres	Standard Error 0.018
Tiotropium (5 μg)	Trough FVC Response on Day 85	0.184 Litres	Standard Error 0.018
Tio+Olo FDC (2.5/5 μg)	Trough FVC Response on Day 85	0.246 Litres	Standard Error 0.018
Tio+Olo FDC (5/5 μg)	Trough FVC Response on Day 85	0.274 Litres	Standard Error 0.019

p-value: 0.017495% CI: [0.011, 0.113]Mixed Models Analysis

p-value: 0.288895% CI: [-0.023, 0.079]Mixed Models Analysis

p-value: <0.000195% CI: [0.159, 0.261]Mixed Models Analysis

p-value: 0.000695% CI: [0.038, 0.141]Mixed Models Analysis

p-value: <0.000195% CI: [0.132, 0.234]Mixed Models Analysis

p-value: 0.009495% CI: [0.017, 0.119]Mixed Models Analysis

p-value: 0.000395% CI: [0.044, 0.146]Mixed Models Analysis

p-value: <0.000195% CI: [0.07, 0.172]Mixed Models Analysis

p-value: <0.000195% CI: [0.064, 0.166]Mixed Models Analysis

p-value: 0.824195% CI: [-0.045, 0.057]Mixed Models Analysis

Source: ClinicalTrials.gov · Data processed: Mar 15, 2026

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

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

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

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

Trough FEV1 Response on Day 170

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

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

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

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

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

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365

Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85

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

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

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

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

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

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

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

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

Trough FEV1 Response on Day 15

Trough FEV1 Response on Day 169

Trough FEV1 Response on Day 365

Trough FEV1 Response on Day 43

Trough FEV1 Response on Day 85

Trough FVC Response on Day 15

Trough FVC Response on Day 170

Trough FVC Response on Day 365

Trough FVC Response on Day 43

Trough FVC Response on Day 85