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

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

Official Title
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A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compared With the Individual Components (2.5 µg and 5 µg Tiotropium, 5 µg Olodaterol) (Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD). [TOnado TM 1]

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: tiotropium + olodaterol
* Drug: tiotropium
* Drug: olodaterol
* Drug: tiotropium
* Drug: tiotropium + olodaterol
* Device: Respimat


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of chronic obstructive pulmonary disease. Relatively stable airway obstruction with post FEV1< 80% predicted normal and post FEV1/FVC <70%. Male or female patients, 40 years of age or older. Smoking history of more than 10 pack years. Exclusion criteria: Significant disease other than COPD Clinically relevant abnormal lab values. History of asthma. Diagnosis of thyrotoxicosis Diagnosis of paroxysmal tachycardia History of myocardial infarction within 1 year of screening visit Unstable or life-threatening cardiac arrhythmia. Hospitalization for heart failure within the past year. Known active tuberculosis. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years History of life-threatening pulmonary obstruction. History of cystic fibrosis. Clinically evident bronchiectasis. History of significant alcohol or drug abuse. Thoracotomy with pulmonary resection Oral ß-adrenergics. Oral corticosteroid medication at unstable doses Regular use of daytime oxygen therapy for more than one hour per day Pulmonary rehabilitation program in the six weeks prior to the screening visit Investigational drug within one month or six half lives (whichever is greater) prior to screening visit Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA Pregnant or nursing women. Women of childbearing potential not using a highly effective method of birth control Patients who are unable to comply with pulmonary medication restrictions

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium+olodaterol low dose FDC<br>Once daily 2 puffs solution for inhalation Respimat | Drug: tiotropium + olodaterol<br>* fixed dose combination<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: tiotropium+olodaterol high dose FDC<br>Once daily 2 puffs solution for inhalation Respimat | Drug: tiotropium + olodaterol<br>* fixed dose combination<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: olodaterol<br>Once daily 2 puffs solution for inhalation Respimat | Drug: olodaterol<br>* one dose only<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: tiotropium low dose<br>Once daily 2 puffs solution for inhalation Respimat | Drug: tiotropium<br>* low dose<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: tiotropium high dose<br>Once daily 2 puffs solution for inhalation Respimat | Drug: tiotropium<br>* high dose<br>Device: Respimat<br>* Respimat inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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 | 
| Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) is the key secondary endpoint. The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. | Day 169 | 
| 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. | 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) 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. | 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) 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. | 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. | 
| 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. | 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 Response 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. | 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 Response 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. | 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85. | 
| Trough FEV1 Response 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. | 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169 | 
| Trough FEV1 Response 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. | 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 | 
| FVC (Forced Vital Capacity) 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. | 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 (Forced Vital Capacity) AUC(0-3h) Response 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. | 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 (Forced Vital Capacity) 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. | 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 (Forced Vital Capacity) 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. | 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. | 
| 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. | 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 Response 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. | 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 Response 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. | 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85 | 
| 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. | 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170 | 
| Trough FVC Response 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. | 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on Day 365. | 
| FEV1 AUC(0-12h) Response in the Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | 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(0-24h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | 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(0-12h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | 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(0-24h) Response in Sub-set of Patients With 24-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | 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. | 
| Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | Day 85 | 
| Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | 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. | Day 365 | 
| Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | Mahler Transitional Dyspnoea Index (TDI) focal score on Day 43 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. | Day 43 | 
| Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | Mahler Transitional Dyspnoea Index (TDI) focal score on Day 85 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. | Day 85 | 
| Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) | Mahler Transitional Dyspnoea Index (TDI) focal score on Day 365 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287). The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. | Day 365 |