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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01431274




Registration number
NCT01431274
Ethics application status
Date submitted
8/09/2011
Date registered
9/09/2011
Date last updated
16/07/2015

Titles & IDs
Public title
Tiotropium+Olodaterol Fixed Dose Combination (FDC) Versus Tiotropium and Olodaterol in Chronic Obstructive Pulmonary Disease (COPD)
Scientific title
A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compared With the Individual Components (2.5 µg and 5 µg Tiotropium, 5 µg Olodaterol) (Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD). [TOnado TM 1]
Secondary ID [1] 0 0
2009-010668-40
Secondary ID [2] 0 0
1237.5
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Disease, Chronic Obstructive 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - tiotropium + olodaterol
Treatment: Drugs - tiotropium
Treatment: Drugs - olodaterol
Treatment: Drugs - tiotropium
Treatment: Drugs - tiotropium + olodaterol
Treatment: Devices - Respimat

Experimental: tiotropium+olodaterol low dose FDC - Once daily 2 puffs solution for inhalation Respimat

Experimental: tiotropium+olodaterol high dose FDC - Once daily 2 puffs solution for inhalation Respimat

Active Comparator: olodaterol - Once daily 2 puffs solution for inhalation Respimat

Active Comparator: tiotropium low dose - Once daily 2 puffs solution for inhalation Respimat

Active Comparator: tiotropium high dose - Once daily 2 puffs solution for inhalation Respimat


Treatment: Drugs: tiotropium + olodaterol
fixed dose combination

Treatment: Drugs: tiotropium
low dose

Treatment: Drugs: olodaterol
one dose only

Treatment: Drugs: tiotropium
high dose

Treatment: Drugs: tiotropium + olodaterol
fixed dose combination

Treatment: Devices: Respimat
Respimat inhaler

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Devices
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
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.
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
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
Primary outcome [3] 0 0
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.
Timepoint [3] 0 0
Day 169
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Day 169
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
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.
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
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
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
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.
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
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
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
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.
Secondary outcome [11] 0 0
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.
Timepoint [11] 0 0
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.
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
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.
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
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.
Secondary outcome [14] 0 0
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.
Timepoint [14] 0 0
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
Secondary outcome [15] 0 0
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.
Timepoint [15] 0 0
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
Secondary outcome [16] 0 0
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.
Timepoint [16] 0 0
1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85
Secondary outcome [17] 0 0
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.
Timepoint [17] 0 0
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
Secondary outcome [18] 0 0
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.
Timepoint [18] 0 0
1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on Day 365.
Secondary outcome [19] 0 0
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.
Timepoint [19] 0 0
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.
Secondary outcome [20] 0 0
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.
Timepoint [20] 0 0
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.
Secondary outcome [21] 0 0
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.
Timepoint [21] 0 0
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.
Secondary outcome [22] 0 0
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.
Timepoint [22] 0 0
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.
Secondary outcome [23] 0 0
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.
Timepoint [23] 0 0
Day 85
Secondary outcome [24] 0 0
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.
Timepoint [24] 0 0
Day 365
Secondary outcome [25] 0 0
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.
Timepoint [25] 0 0
Day 43
Secondary outcome [26] 0 0
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.
Timepoint [26] 0 0
Day 85
Secondary outcome [27] 0 0
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.
Timepoint [27] 0 0
Day 365

Eligibility
Key inclusion criteria
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.
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
1237.5.61001 Boehringer Ingelheim Investigational Site - Toorak Gardens
Recruitment hospital [2] 0 0
1237.5.61002 Boehringer Ingelheim Investigational Site - Woodville
Recruitment hospital [3] 0 0
1237.5.61004 Boehringer Ingelheim Investigational Site - Frankston
Recruitment postcode(s) [1] 0 0
- Toorak Gardens
Recruitment postcode(s) [2] 0 0
- Woodville
Recruitment postcode(s) [3] 0 0
- Frankston
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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Colorado
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Connecticut
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Florida
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Illinois
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Louisiana
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Maine
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Maryland
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Michigan
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Nebraska
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Oklahoma
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Rhode Island
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Virginia
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Washington
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West Virginia
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Argentina
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Buenos Aires
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Argentina
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Caba
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Argentina
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Capital Federal
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Argentina
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Cuidad Autonoma de Buenos Airess A
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Argentina
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Mar del Plata
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Mendoza
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Monte Grande
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Argentina
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Quilmes
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Rosario
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San Miguel de Tucuman
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Argentina
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Rousse
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Shumen
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Cvikov
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Pori
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Nantes
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France
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Nîmes cedex 9
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France
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Perpignan
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France
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Bamberg
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Berlin
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Erfurt
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Hamburg
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Koblenz
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Germany
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Neu-Isenburg
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Germany
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Oschersleben
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Rüdersdorf
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Weinheim
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Wiesloch
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Guatemala
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Deszk
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Kapuvar
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Szombathely
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Hungary
State/province [98] 0 0
Törökbalint
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India
State/province [99] 0 0
Ahmedabad
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India
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Bangalore
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India
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Coimbatore
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India
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Hyderabad
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India
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Jaipur
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India
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Mysore
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India
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Pune
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Cagliari
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Italy
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Genova
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Italy
State/province [108] 0 0
Montescano (PV)
Country [109] 0 0
Italy
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Monza
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Parma
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Italy
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Pisa
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Japan
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Aoba-ku, Sendai, Miyagi
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Japan
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Asahikawa, Hokkaido
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Japan
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Bunkyo-ku, Tokyo
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Japan
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Chuo-ku, Kumamoto, Kumamoto
Country [116] 0 0
Japan
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Gifu, Gifu
Country [117] 0 0
Japan
State/province [117] 0 0
Hakata-ku, Fukuoka, Fukuoka
Country [118] 0 0
Japan
State/province [118] 0 0
Hamamatsushi, Shizuoka
Country [119] 0 0
Japan
State/province [119] 0 0
Himeji, Hyogo
Country [120] 0 0
Japan
State/province [120] 0 0
Ikoma, Nara
Country [121] 0 0
Japan
State/province [121] 0 0
Inashiki-gun, Ibaraki
Country [122] 0 0
Japan
State/province [122] 0 0
Itabashi-ku, Tokyo
Country [123] 0 0
Japan
State/province [123] 0 0
Jonan-ku, Fukuoka, Fukuoka
Country [124] 0 0
Japan
State/province [124] 0 0
Kagoshima, Kagoshima,
Country [125] 0 0
Japan
State/province [125] 0 0
Kagoshima, Kagoshima
Country [126] 0 0
Japan
State/province [126] 0 0
Kamogawa, Chiba
Country [127] 0 0
Japan
State/province [127] 0 0
Kishiwada, Osaka
Country [128] 0 0
Japan
State/province [128] 0 0
Kitakyusyu,Fukuoka
Country [129] 0 0
Japan
State/province [129] 0 0
Koga, Fukuoka
Country [130] 0 0
Japan
State/province [130] 0 0
Komaki, Aichi
Country [131] 0 0
Japan
State/province [131] 0 0
Koshi, Kumamoto
Country [132] 0 0
Japan
State/province [132] 0 0
koto-ku, Tokyo
Country [133] 0 0
Japan
State/province [133] 0 0
Kuki, Saitama
Country [134] 0 0
Japan
State/province [134] 0 0
Kure, Hiroshima
Country [135] 0 0
Japan
State/province [135] 0 0
Kurume, Fukuoka
Country [136] 0 0
Japan
State/province [136] 0 0
Matsumoto, Nagano
Country [137] 0 0
Japan
State/province [137] 0 0
Matsusaka, Mie
Country [138] 0 0
Japan
State/province [138] 0 0
Minami-ku. Fukuoka, Fukuoka
Country [139] 0 0
Japan
State/province [139] 0 0
Morioka, Iwate
Country [140] 0 0
Japan
State/province [140] 0 0
Nagoya, Aichi
Country [141] 0 0
Japan
State/province [141] 0 0
Naka-gun, Ibaraki
Country [142] 0 0
Japan
State/province [142] 0 0
Okinawa, Urasoe
Country [143] 0 0
Japan
State/province [143] 0 0
Sayama, Osaka
Country [144] 0 0
Japan
State/province [144] 0 0
Sendai, Miyagi
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Japan
State/province [145] 0 0
Seto, Aichi
Country [146] 0 0
Japan
State/province [146] 0 0
Shinagawa, Tokyo
Country [147] 0 0
Japan
State/province [147] 0 0
Shinjyuku-ku, Tokyo
Country [148] 0 0
Japan
State/province [148] 0 0
Takamatsu, Kagawa
Country [149] 0 0
Japan
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Wakayama, Wakayama
Country [150] 0 0
Japan
State/province [150] 0 0
Yanagawa-shi, Fukuoka,
Country [151] 0 0
Japan
State/province [151] 0 0
Yokohama, Kanagawa
Country [152] 0 0
Korea, Republic of
State/province [152] 0 0
Bucheon
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Korea, Republic of
State/province [153] 0 0
Daegu
Country [154] 0 0
Korea, Republic of
State/province [154] 0 0
Seoul
Country [155] 0 0
Korea, Republic of
State/province [155] 0 0
Suwon
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Korea, Republic of
State/province [156] 0 0
Wonju
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Mexico
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Hermosillo
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Mexico
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Mexico
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Mexico
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Monterrey
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Mexico
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Tijuana
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Netherlands
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Almelo
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Breda
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Netherlands
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Eindhoven
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Netherlands
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Harderwijk
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Netherlands
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Heerlen
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Netherlands
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Hengelo
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Netherlands
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Hoorn
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Netherlands
State/province [168] 0 0
Nieuwegein
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Netherlands
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Veldhoven
Country [170] 0 0
Netherlands
State/province [170] 0 0
Zutphen
Country [171] 0 0
New Zealand
State/province [171] 0 0
Dunedin
Country [172] 0 0
New Zealand
State/province [172] 0 0
Greenlane East Auckland NZ
Country [173] 0 0
Portugal
State/province [173] 0 0
Amadora
Country [174] 0 0
Portugal
State/province [174] 0 0
Coimbra
Country [175] 0 0
Portugal
State/province [175] 0 0
Lisboa
Country [176] 0 0
Portugal
State/province [176] 0 0
Porto
Country [177] 0 0
Portugal
State/province [177] 0 0
Vila Nova de Gaia
Country [178] 0 0
Portugal
State/province [178] 0 0
Viseu
Country [179] 0 0
Russian Federation
State/province [179] 0 0
Gatchina (Leningradskaya oblast)
Country [180] 0 0
Russian Federation
State/province [180] 0 0
Kazan
Country [181] 0 0
Russian Federation
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Moscow
Country [182] 0 0
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St. Petersburg
Country [183] 0 0
Slovenia
State/province [183] 0 0
Golnik
Country [184] 0 0
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State/province [184] 0 0
Istanbul
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Turkey
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Izmir
Country [186] 0 0
Turkey
State/province [186] 0 0
Izmit
Country [187] 0 0
Turkey
State/province [187] 0 0
Mersin

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Boehringer Ingelheim
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The overall objective of this study is to assess the efficacy and safety of 52 weeks once
daily treatment with orally inhaled tiotropium + olodaterol FDC (delivered by the RESPIMAT
Inhaler) compared with the individual components ( tiotropium, olodaterol) (delivered by the
RESPIMAT Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).
Trial website
https://clinicaltrials.gov/show/NCT01431274
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Boehringer Ingelheim
Address 0 0
Boehringer Ingelheim
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications