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Combination of Orally Inhaled BI1744CL/Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease ( COPD)

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT00696020
Collaborator
(none)
360
Enrollment
37
Locations
4
Arms
9.7
Patients Per Site

Study Details

Study Description

Brief Summary

The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL administered with 5 micrograms tiotropium bromide solution for inhalation, delivered by the Respimat inhaler, once daily for four weeks in patients with chronic obstructive pulmonary disease (COPD).

Condition or Disease Intervention/Treatment Phase
  • Drug: BI 1744 CL/tiotropium bromide fixed dose combination
  • Drug: tiotropium bromide
  • Device: Respimat® Inhaler
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
360 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Randomised, Double-Blind, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 3 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination With 5 Microgram Tiotropium Bromide (Delivered by the Respimat Inhaler) Compared With 5 Microgram Tiotropium Bromide Monoproduct (Delivered by the Respimat Inhaler) in Patients With COPD
Study Start Date :
Jun 1, 2008
Actual Primary Completion Date :
Feb 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: BI 1744 CL low dose/tiotropium bromide

BI 1744 CL low dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Drug: BI 1744 CL/tiotropium bromide fixed dose combination
BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Device: Respimat® Inhaler
Experimental: BI1744CL medium dose/tiotropium bromide

BI 1744 CL medium dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Drug: BI 1744 CL/tiotropium bromide fixed dose combination
BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Device: Respimat® Inhaler
Experimental: BI 1744 CL high dose/tiotropium bromide

BI 1744 CL high dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Drug: BI 1744 CL/tiotropium bromide fixed dose combination
BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Device: Respimat® Inhaler
Experimental: tiotropium bromide

tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Drug: tiotropium bromide
tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

Device: Respimat® Inhaler

Outcome Measures

Primary Outcome Measures

  1. Trough FEV1 Response [L] After 4 Weeks of Treatment [Baseline and 4 weeks]

    Trough FEV1 (Forced expiratory volume in 1 second) was defined as the mean of the two FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).

Secondary Outcome Measures

  1. Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment. [Baseline, 1 week and 2 weeks]

    Trough FEV1 (forced expiratory volume in 1 second) was defined as the mean of the 2 FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 15.

  2. Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment [Baseline, 1 week, 2 weeks and 4 weeks]

    Trough FVC (forced vital capacity) was defined as the mean of the 2 FVC values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FVC response was defined as the change from baseline in trough FVC. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  3. FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment [1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks]

    Response is defined as change from the baseline value. AUC(0-3h) (area under the curve) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  4. FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment. [1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks]

    FVC (forced vital capacity) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  5. PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment. [1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks]

    PEF (peak expiratory flow rate L/min) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) will be calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  6. FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment [1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)]

    FEV1 (forced expiratory volume in 1 second) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).

  7. FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment [1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)]

    FVC (forced vital capacity) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  8. PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment [1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)]

    PEF (peak expiratory flow rate L/min) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  9. FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment [5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks]

    FEV1 (forced expiratory volume in 1 second) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  10. FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment [5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks]

    FVC (forced vital capacity) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  11. PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment [5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks]

    PEF (peak expiratory flow rate L/min) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  12. FEV1 and PEF (Unsupervised) AUC(0-6h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment [After first administration, 1 week, 2 weeks and 4 weeks]

    AUC(0-6h) for FEV1, and PEF (unsupervised) were not studied because the pertinent information from the unsupervised pulmonary function tests was for the time interval from 9 to 12 hours post-dosing.

  13. FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment [6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks]

    FEV1 (forced expiratory volume in 1 second) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  14. PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment [6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks]

    PEF (peak expiratory flow rate L/min) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.

  15. Weekly Mean Pre-dose Morning PEF [L/Min] [Throughout the 4 week treatment period]

    The patient will record twice daily peak flow measurements using an Asthma Monitor®Am2+ (AM2+) device. Morning measurements will be performed immediately upon arising after the patient has cleared out mucus, prior to administration of trial and/or rescue medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  16. Weekly Mean Evening PEF [L/Min] [Throughout the 4 weeks treatment period]

    The patient will record twice daily peak flow measurements using an AM2+ device. The evening measurement will be performed at bedtime. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  17. Weekly Mean Number of Occasions of Rescue Therapy Used Per Day [Throughout the 4 weeks treatment period]

    The means are adjusted, Based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  18. Physician's Global Evaluation [1 week, 2 weeks and 4 weeks]

    Measured a 8-point scale, from 1 (poor) to 8 (excellent), as judged by the physician, over 4 weeks of treatment. The physician made a global evaluation at the end of the Baseline Period (Test Day 1) and at each visit thereafter. These assessments were made prior to pulmonary function testing and reflected the physician's opinion of the patient's overall clinical condition. This evaluation was based on the need for concomitant medication, number and severity of COPD exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).

  19. Patient's Global Rating [4 weeks]

    Patient's Global Rating at the end of the 4 week treatment period. Patients rated their health (respiratory condition) at Day 29 (compared to the day before they commenced treatment with study medication) on a 7-point scale as "very much better (1), much better (2), a little better (3), no change (4), a little worse (5), much worse (6), or very much worse (7)". The assessment was made prior to pulmonary function testing and all other study procedures. The Patient's Global Rating was also completed before the Physician's Global Evaluation. The means are adjusted, based on an ANCOVA with terms for treatment, centre (centre random, treatment effect fixed).

  20. Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities [From first dose up to 21 days after last dose of study medication.]

    Possible clinically significant anormalities (laboratory data); marked changes from baseline for vital signs, notable change in ECG and new onset of ECG abnormalities. New abnormal findings or worsening of baseline conditions were reported as Adverse Events (AEs). All AEs with an onset after the first dose of study medication up to 21 days after the last dose of study medication were to have been assigned to the Treatment Period.

  21. Cmax,ss Olodaterol [pg/mL] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss) after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.

  22. Tmax,ss Olodaterol [h] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Time from last dosing to maximum concentration of Olodaterol in plasma at steady state (tmax,ss) after 4 weeks treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.

  23. AUC(0-1h,ss) Olodaterol [pg*h/mL] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Area under the concentration-time curve of Olodaterol in plasma at steady state (AUC(0-1h,ss)) from 0 to 1 hour post dosing after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.

  24. Cmax,ss Tiotropium [pg/mL] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss) after 4 weeks treatment.

  25. Tmax,ss Tiotropium [h] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Time from last dosing to maximum concentration of Tiotropium in plasma at steady state (tmax,ss) after 4 weeks of treatment.

  26. AUC(0-3h,ss) Tiotropium [pg*h/mL] [Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.]

    Area under the concentration-time curve of Tiotropium at steady state (AUC(0-3h,ss)) from 0 to 3 hours post dosing after 4 weeks of treatment.

Eligibility Criteria

Criteria

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

  1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions

  2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1 greater or equal 30% of predicted normal and <80% of predicted normal and a post-bronchodilator FEV1 / FVC <70% at Visit 1

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

  2. Patients must be current or ex-smokers with a smoking history of more than 10 pack years

  3. Patients must be able to perform technically acceptable pulmonary function tests and PEF measurements, and must be able to maintain records (Patient Daily e-Diary) during the study period as required in the protocol

  4. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a metered dose inhaler (MDI).

Further inclusion criteria apply

Exclusion Criteria:

  1. Patients with a significant disease other than COPD

  2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis;

  3. Patients with a history of asthma or a total blood eosinophil count >= 600/mm3.

  4. Patients with any of the following conditions:a diagnosis of thyrotoxicosis, a diagnosis of paroxysmal tachycardia (>100 beats per minute), a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTcF* interval > 450 ms), a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT Syndrome)

  5. Patients with any of the following conditions:a history of myocardial infarction within 1 year of screening visit (Visit 1), a diagnosis of clinically relevant cardiac arrhythmia, known active tuberculosis, a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years, a history of life-threatening pulmonary obstruction, a history of cystic fibrosis, clinically evident bronchiectasis, a history of significant alcohol or drug abuse

  6. Patients who have undergone thoracotomy with pulmonary resection

  7. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits.

  8. Pregnant or nursing women

  9. Women of childbearing potential not using two effective method of birth control (one barrier and one non-barrier). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years

  10. Patients who have previously been randomized in this study or are currently participating in another study

  11. Patients who are unable to comply with pulmonary medication restrictions prior to randomization

  12. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit

Further exclusion criteria apply

Contacts and Locations

Locations

Site City State Country Postal Code
1 1237.4.0118 Boehringer Ingelheim Investigational Site Riverside California United States
2 1237.4.0103 Boehringer Ingelheim Investigational Site San Diego California United States
3 1237.4.0115 Boehringer Ingelheim Investigational Site Wheat Ridge Colorado United States
4 1237.4.0105 Boehringer Ingelheim Investigational Site Clearwater Florida United States
5 1237.4.0110 Boehringer Ingelheim Investigational Site Deland Florida United States
6 1237.4.0117 Boehringer Ingelheim Investigational Site Tampa Florida United States
7 1237.4.0104 Boehringer Ingelheim Investigational Site Coeur d'Alene Idaho United States
8 1237.4.0120 Boehringer Ingelheim Investigational Site Edina Minnesota United States
9 1237.4.0112 Boehringer Ingelheim Investigational Site Minneapolis Minnesota United States
10 1237.4.0119 Boehringer Ingelheim Investigational Site St. Charles Missouri United States
11 1237.4.0114 Boehringer Ingelheim Investigational Site Raleigh North Carolina United States
12 1237.4.0102 Boehringer Ingelheim Investigational Site Philadelphia Pennsylvania United States
13 1237.4.0111 Boehringer Ingelheim Investigational Site Charleston South Carolina United States
14 1237.4.0106 Boehringer Ingelheim Investigational Site Spartanburg South Carolina United States
15 1237.4.0107 Boehringer Ingelheim Investigational Site Spartanburg South Carolina United States
16 1237.4.0123 Boehringer Ingelheim Investigational Site Knoxville Tennessee United States
17 1237.4.0122 Boehringer Ingelheim Investigational Site Killeen Texas United States
18 1237.4.0109 Boehringer Ingelheim Investigational Site New Braunfels Texas United States
19 1237.4.0108 Boehringer Ingelheim Investigational Site Richmond Virginia United States
20 1237.4.0116 Boehringer Ingelheim Investigational Site Spokane Washington United States
21 1237.4.0121 Boehringer Ingelheim Investigational Site Tacoma Washington United States
22 1237.4.0101 Boehringer Ingelheim Investigational Site Morgantown West Virginia United States
23 1237.4.0203 Boehringer Ingelheim Investigational Site Winnipeg Manitoba Canada
24 1237.4.0201 Boehringer Ingelheim Investigational Site Mississauga Ontario Canada
25 1237.4.0202 Boehringer Ingelheim Investigational Site Toronto Ontario Canada
26 1237.4.0205 Boehringer Ingelheim Investigational Site Toronto Ontario Canada
27 1237.4.0208 Boehringer Ingelheim Investigational Site Toronto Ontario Canada
28 1237.4.0206 Boehringer Ingelheim Investigational Site Sainte-Foy Quebec Canada
29 1237.4.0204 Boehringer Ingelheim Investigational Site Sherbrooke Quebec Canada
30 1237.4.0207 Boehringer Ingelheim Investigational Site Saskatoon Saskatchewan Canada
31 1237.4.4903 Boehringer Ingelheim Investigational Site Berlin Germany
32 1237.4.4907 Boehringer Ingelheim Investigational Site Erfurt Germany
33 1237.4.4902 Boehringer Ingelheim Investigational Site Gauting Germany
34 1237.4.4908 Boehringer Ingelheim Investigational Site Halle Germany
35 1237.4.4906 Boehringer Ingelheim Investigational Site Neuruppin Germany
36 1237.4.4904 Boehringer Ingelheim Investigational Site Rüdersdorf Germany
37 1237.4.4901 Boehringer Ingelheim Investigational Site Weinheim Germany

Sponsors and Collaborators

  • Boehringer Ingelheim

Investigators

  • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00696020
Other Study ID Numbers:
  • 1237.4
  • EudraCT No: 2007-005087-26
First Posted:
Jun 12, 2008
Last Update Posted:
Aug 13, 2015
Last Verified:
Jul 1, 2015
Additional relevant MeSH terms:
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Bromides
Tiotropium Bromide
Olodaterol

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail A randomised, double-blind, parallel group study. Each patient received their randomised treatment for 28 days.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Period Title: Overall Study
STARTED 90 89 93 88
COMPLETED 86 87 90 84
NOT COMPLETED 4 2 3 4

Baseline Characteristics

Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg Total
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Total of all reporting groups
Overall Participants 90 89 93 88 360
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
61.87
(8.50)
64.44
(9.18)
64.19
(9.59)
62.66
(8.86)
63.30
(9.07)
Sex: Female, Male (Count of Participants)
Female
47
52.2%
33
37.1%
45
48.4%
39
44.3%
164
45.6%
Male
43
47.8%
56
62.9%
48
51.6%
49
55.7%
196
54.4%

Outcome Measures

1. Primary Outcome
Title Trough FEV1 Response [L] After 4 Weeks of Treatment
Description Trough FEV1 (Forced expiratory volume in 1 second) was defined as the mean of the two FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).
Time Frame Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set (FAS). The FAS consisted of all patients who received at least 1 dose of study medication and had baseline data (pre-treatment at the end of the 2-week baseline) for at least 1 efficacy endpoint. For this trial all randomized and treated patients were included in the FAS.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Least Squares Mean (Standard Error) [L]
0.110
(0.021)
0.134
(0.021)
0.143
(0.020)
0.168
(0.021)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3791
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.024
Confidence Interval (2-Sided) 95%
-0.029 to 0.076
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.027
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.2133
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.033
Confidence Interval (2-Sided) 95%
-0.019 to 0.085
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.027
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0337
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.057
Confidence Interval (2-Sided) 95%
0.004 to 0.110
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.027
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
2. Secondary Outcome
Title Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.
Description Trough FEV1 (forced expiratory volume in 1 second) was defined as the mean of the 2 FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 15.
Time Frame Baseline, 1 week and 2 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 8
0.093
(0.020)
0.149
(0.020)
0.154
(0.019)
0.166
(0.020)
Day 15
0.099
(0.020)
0.141
(0.020)
0.159
(0.020)
0.154
(0.021)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1163
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.042
Confidence Interval (2-Sided) 95%
-0.010 to 0.093
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.026
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0224
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.060
Confidence Interval (2-Sided) 95%
0.009 to 0.111
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.026
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0380
Comments Type I error was controlled by a closed stepwise procedure.
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.055
Confidence Interval (2-Sided) 95%
0.003 to 0.107
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.026
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
3. Secondary Outcome
Title Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment
Description Trough FVC (forced vital capacity) was defined as the mean of the 2 FVC values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FVC response was defined as the change from baseline in trough FVC. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame Baseline, 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 8
0.156
(0.033)
0.215
(0.033)
0.265
(0.032)
0.275
(0.033)
Day 15
0.171
(0.034)
0.196
(0.034)
0.280
(0.033)
0.285
(0.034)
Day 29
0.189
(0.036)
0.191
(0.036)
0.288
(0.036)
0.306
(0.037)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9573
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.002
Confidence Interval (2-Sided) 95%
-0.089 to 0.094
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.047
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0321
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.099
Confidence Interval (2-Sided) 95%
0.009 to 0.189
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.046
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0125
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.117
Confidence Interval (2-Sided) 95%
0.025 to 0.209
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.047
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
4. Secondary Outcome
Title FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
Description Response is defined as change from the baseline value. AUC(0-3h) (area under the curve) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
0.161
(0.016)
0.201
(0.016)
0.229
(0.016)
0.225
(0.016)
Day 8
0.204
(0.024)
0.289
(0.024)
0.302
(0.023)
0.315
(0.024)
Day 15
0.201
(0.024)
0.288
(0.024)
0.305
(0.024)
0.309
(0.025)
Day 29
0.191
(0.023)
0.276
(0.023)
0.270
(0.022)
0.316
(0.023)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0052
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.085
Confidence Interval (2-Sided) 95%
0.026 to 0.145
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.030
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0086
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.079
Confidence Interval (2-Sided) 95%
0.020 to 0.138
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.030
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.125
Confidence Interval (2-Sided) 95%
0.066 to 0.185
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.030
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
5. Secondary Outcome
Title FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.
Description FVC (forced vital capacity) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
0.268
(0.032)
0.331
(0.032)
0.413
(0.031)
0.410
(0.032)
Day 8
0.310
(0.042)
0.441
(0.042)
0.493
(0.041)
0.537
(0.042)
Day 15
0.327
(0.044)
0.437
(0.044)
0.513
(0.043)
0.554
(0.044)
Day 29
0.308
(0.043)
0.424
(0.043)
0.492
(0.043)
0.547
(0.044)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0384
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.116
Confidence Interval (2-Sided) 95%
0.006 to 0.225
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.056
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0009
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.184
Confidence Interval (2-Sided) 95%
0.076 to 0.292
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.055
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.239
Confidence Interval (2-Sided) 95%
0.130 to 0.349
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.056
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
6. Secondary Outcome
Title PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.
Description PEF (peak expiratory flow rate L/min) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) will be calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
21.973
(3.596)
35.738
(3.614)
35.350
(3.533)
40.027
(3.646)
Day 8
29.701
(4.966)
52.816
(4.973)
49.722
(4.875)
53.448
(5.025)
Day 15
32.108
(5.115)
54.527
(5.130)
53.829
(5.022)
54.289
(5.180)
Day 29
29.734
(4.889)
52.091
(4.912)
48.503
(4.802)
56.688
(4.956)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0010
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.357
Confidence Interval (2-Sided) 95%
9.057 to 35.657
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.760
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0053
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 18.769
Confidence Interval (2-Sided) 95%
5.613 to 31.924
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.687
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 26.954
Confidence Interval (2-Sided) 95%
13.565 to 40.343
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.805
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
7. Secondary Outcome
Title FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment
Description FEV1 (forced expiratory volume in 1 second) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).
Time Frame 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Least Squares Mean (Standard Error) [L]
0.194
(0.023)
0.282
(0.023)
0.280
(0.023)
0.322
(0.024)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0048
Comments
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.027 to 0.149
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.031
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0056
Comments
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.086
Confidence Interval (2-Sided) 95%
0.025 to 0.146
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.031
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, and centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.128
Confidence Interval (2-Sided) 95%
0.066 to 0.189
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.031
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
8. Secondary Outcome
Title FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment
Description FVC (forced vital capacity) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Least Squares Mean (Standard Error) [L]
0.309
(0.044)
0.429
(0.044)
0.492
(0.043)
0.547
(0.044)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0332
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.120
Confidence Interval (2-Sided) 95%
0.010 to 0.230
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.056
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0011
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.183
Confidence Interval (2-Sided) 95%
0.074 to 0.292
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.055
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.238
Confidence Interval (2-Sided) 95%
0.128 to 0.349
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.056
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
9. Secondary Outcome
Title PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment
Description PEF (peak expiratory flow rate L/min) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Least Squares Mean (Standard Error) [L]
30.576
(4.933)
53.443
(4.956)
50.319
(4.845)
58.368
(5.001)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0009
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.867
Confidence Interval (2-Sided) 95%
9.462 to 36.272
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.813
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0036
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 19.743
Confidence Interval (2-Sided) 95%
6.484 to 33.002
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.739
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 27.793
Confidence Interval (2-Sided) 95%
14.298 to 41.287
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.859
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
10. Secondary Outcome
Title FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
Description FEV1 (forced expiratory volume in 1 second) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
0.249
(0.019)
0.284
(0.019)
0.311
(0.019)
0.321
(0.019)
Day 8
0.276
(0.025)
0.359
(0.025)
0.378
(0.024)
0.397
(0.025)
Day 15
0.276
(0.026)
0.361
(0.026)
0.391
(0.026)
0.386
(0.027)
Day 29
0.266
(0.024)
0.353
(0.024)
0.348
(0.024)
0.410
(0.024)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0079
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.023 to 0.152
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.033
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0120
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.082
Confidence Interval (2-Sided) 95%
0.018 to 0.146
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.032
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.144
Confidence Interval (2-Sided) 95%
0.080 to 0.209
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.033
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
11. Secondary Outcome
Title FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
Description FVC (forced vital capacity) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
0.428
(0.037)
0.476
(0.037)
0.576
(0.036)
0.583
(0.037)
Day 8
0.437
(0.043)
0.560
(0.043)
0.615
(0.042)
0.690
(0.043)
Day 15
0.465
(0.047)
0.586
(0.047)
0.648
(0.046)
0.697
(0.047)
Day 29
0.431
(0.045)
0.562
(0.045)
0.634
(0.044)
0.696
(0.046)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0296
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.131
Confidence Interval (2-Sided) 95%
0.013 to 0.249
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.060
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0007
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.204
Confidence Interval (2-Sided) 95%
0.087 to 0.320
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.059
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.265
Confidence Interval (2-Sided) 95%
0.147 to 0.383
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.060
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
12. Secondary Outcome
Title PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
Description PEF (peak expiratory flow rate L/min) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Day 1
43.051
(4.445)
53.801
(4.474)
53.853
(4.370)
62.360
(4.510)
Day 8
47.819
(5.213)
69.792
(5.227)
69.254
(5.118)
73.828
(5.279)
Day 15
48.129
(6.897)
79.890
(6.930)
71.916
(6.775)
73.886
(6.992)
Day 29
47.104
(5.088)
70.519
(5.114)
65.800
(4.999)
76.461
(5.159)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0010
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 23.414
Confidence Interval (2-Sided) 95%
9.529 to 37.300
Parameter Dispersion Type: Standard Error of the Mean
Value: 7.057
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0078
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 18.695
Confidence Interval (2-Sided) 95%
4.961 to 32.430
Parameter Dispersion Type: Standard Error of the Mean
Value: 6.981
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 29.357
Confidence Interval (2-Sided) 95%
15.379 to 43.335
Parameter Dispersion Type: Standard Error of the Mean
Value: 7.105
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
13. Secondary Outcome
Title FEV1 and PEF (Unsupervised) AUC(0-6h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
Description AUC(0-6h) for FEV1, and PEF (unsupervised) were not studied because the pertinent information from the unsupervised pulmonary function tests was for the time interval from 9 to 12 hours post-dosing.
Time Frame After first administration, 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 0 0 0 0
14. Secondary Outcome
Title FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment
Description FEV1 (forced expiratory volume in 1 second) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 87 88 86 83
Day 1
0.143
(0.031)
0.181
(0.031)
0.209
(0.031)
0.175
(0.032)
Day 8
0.169
(0.035)
0.203
(0.035)
0.219
(0.035)
0.172
(0.036)
Day 15
0.142
(0.038)
0.197
(0.038)
0.205
(0.038)
0.169
(0.039)
Day 29
0.145
(0.034)
0.189
(0.034)
0.193
(0.034)
0.180
(0.035)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3517
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.044
Confidence Interval (2-Sided) 95%
-0.049 to 0.138
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.048
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3171
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.048
Confidence Interval (2-Sided) 95%
-0.046 to 0.143
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.048
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.4654
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.035
Confidence Interval (2-Sided) 95%
-0.060 to 0.130
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.048
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
15. Secondary Outcome
Title PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment
Description PEF (peak expiratory flow rate L/min) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29.
Time Frame 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 87 88 86 83
Day 1
29.261
(5.245)
41.838
(5.197)
45.179
(5.253)
41.852
(5.360)
Day 8
30.139
(5.690)
47.625
(5.643)
48.503
(5.704)
47.924
(5.819)
Day 15
27.512
(5.680)
42.179
(5.627)
52.249
(5.688)
45.798
(5.803)
Day 29
28.396
(5.469)
41.502
(5.438)
48.212
(5.497)
47.289
(5.606)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/2 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0899
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 13.106
Confidence Interval (2-Sided) 95%
-2.055 to 28.267
Parameter Dispersion Type: Standard Error of the Mean
Value: 7.704
Estimation Comments 2 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/5 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0111
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 19.817
Confidence Interval (2-Sided) 95%
4.549 to 35.084
Parameter Dispersion Type: Standard Error of the Mean
Value: 7.759
Estimation Comments 5 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 µg Tiotropium, Tiotropium+Olodaterol 5/10 μg
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0166
Comments
Method ANCOVA
Comments terms for baseline, treatment, centre (centre random, all other effects fixed)
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 18.893
Confidence Interval (2-Sided) 95%
3.458 to 34.329
Parameter Dispersion Type: Standard Error of the Mean
Value: 7.844
Estimation Comments 10 µg Olodaterol + 5 µg Tiotropium minus 5 µg Tiotropium.
16. Secondary Outcome
Title Weekly Mean Pre-dose Morning PEF [L/Min]
Description The patient will record twice daily peak flow measurements using an Asthma Monitor®Am2+ (AM2+) device. Morning measurements will be performed immediately upon arising after the patient has cleared out mucus, prior to administration of trial and/or rescue medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame Throughout the 4 week treatment period

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 89 88 90 83
Week 1
227.81
(3.198)
244.43
(3.208)
248.84
(3.174)
248.76
(3.310)
Week 2
228.57
(3.401)
240.87
(3.415)
249.99
(3.377)
247.77
(3.524)
Week 3
228.82
(3.663)
239.61
(3.684)
249.39
(3.639)
248.33
(3.800)
Week 4
226.49
(3.678)
234.14
(3.699)
249.17
(3.654)
247.30
(3.816)
17. Secondary Outcome
Title Weekly Mean Evening PEF [L/Min]
Description The patient will record twice daily peak flow measurements using an AM2+ device. The evening measurement will be performed at bedtime. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame Throughout the 4 weeks treatment period

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 89 88 92 84
Week 1
249.10
(3.419)
260.86
(3.425)
267.47
(3.360)
268.58
(3.510)
Week 2
247.10
(3.804)
260.73
(3.814)
267.31
(3.738)
266.40
(3.909)
Week 3
249.78
(3.765)
258.20
(3.791)
268.16
(3.702)
265.67
(3.884)
Week 4
246.77
(3.777)
253.12
(3.803)
266.61
(3.714)
265.50
(3.896)
18. Secondary Outcome
Title Weekly Mean Number of Occasions of Rescue Therapy Used Per Day
Description The means are adjusted, Based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame Throughout the 4 weeks treatment period

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 89 89 92 84
Week 1
1.905
(0.155)
1.512
(0.155)
1.504
(0.152)
1.669
(0.159)
Week 2
1.784
(0.178)
1.610
(0.177)
1.476
(0.175)
1.477
(0.182)
Week 3
1.947
(0.183)
1.650
(0.182)
1.492
(0.180)
1.563
(0.187)
Week 4
2.017
(0.172)
1.615
(0.172)
1.602
(0.169)
1.482
(0.176)
19. Secondary Outcome
Title Physician's Global Evaluation
Description Measured a 8-point scale, from 1 (poor) to 8 (excellent), as judged by the physician, over 4 weeks of treatment. The physician made a global evaluation at the end of the Baseline Period (Test Day 1) and at each visit thereafter. These assessments were made prior to pulmonary function testing and reflected the physician's opinion of the patient's overall clinical condition. This evaluation was based on the need for concomitant medication, number and severity of COPD exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).
Time Frame 1 week, 2 weeks and 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 92 88
Day 8
5.139
(0.102)
5.102
(0.102)
5.185
(0.100)
5.149
(0.102)
Day 15
5.272
(0.113)
5.130
(0.113)
5.382
(0.111)
5.104
(0.113)
Day 29
5.264
(0.115)
5.295
(0.115)
5.447
(0.113)
5.252
(0.115)
20. Secondary Outcome
Title Patient's Global Rating
Description Patient's Global Rating at the end of the 4 week treatment period. Patients rated their health (respiratory condition) at Day 29 (compared to the day before they commenced treatment with study medication) on a 7-point scale as "very much better (1), much better (2), a little better (3), no change (4), a little worse (5), much worse (6), or very much worse (7)". The assessment was made prior to pulmonary function testing and all other study procedures. The Patient's Global Rating was also completed before the Physician's Global Evaluation. The means are adjusted, based on an ANCOVA with terms for treatment, centre (centre random, treatment effect fixed).
Time Frame 4 weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 86 87 90 84
Least Squares Mean (Standard Error) [units on a patient's global rating score]
2.866
(0.112)
2.598
(0.111)
2.368
(0.109)
2.377
(0.113)
21. Secondary Outcome
Title Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities
Description Possible clinically significant anormalities (laboratory data); marked changes from baseline for vital signs, notable change in ECG and new onset of ECG abnormalities. New abnormal findings or worsening of baseline conditions were reported as Adverse Events (AEs). All AEs with an onset after the first dose of study medication up to 21 days after the last dose of study medication were to have been assigned to the Treatment Period.
Time Frame From first dose up to 21 days after last dose of study medication.

Outcome Measure Data

Analysis Population Description
Treated Set.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 90 89 93 88
Number [participants]
1
1.1%
0
0%
0
0%
0
0%
22. Secondary Outcome
Title Cmax,ss Olodaterol [pg/mL]
Description Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss) after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients. A patient was considered to be not evaluable if the patient had a protocol violation relevant to the evaluation of PK or had insufficient data.
Arm/Group Title Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 42 59
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]
4.39
(49.2)
6.87
(56.1)
23. Secondary Outcome
Title Tmax,ss Olodaterol [h]
Description Time from last dosing to maximum concentration of Olodaterol in plasma at steady state (tmax,ss) after 4 weeks treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients.
Arm/Group Title Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 42 59
Median (Full Range) [hours]
0.167
0.183
24. Secondary Outcome
Title AUC(0-1h,ss) Olodaterol [pg*h/mL]
Description Area under the concentration-time curve of Olodaterol in plasma at steady state (AUC(0-1h,ss)) from 0 to 1 hour post dosing after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients.
Arm/Group Title Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 28 52
Geometric Mean (Geometric Coefficient of Variation) [pg*h/mL]
3.97
(49.4)
5.82
(50.5)
25. Secondary Outcome
Title Cmax,ss Tiotropium [pg/mL]
Description Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss) after 4 weeks treatment.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 78 78 73 73
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]
13.3
(75.3)
13.9
(64.7)
12.4
(69.7)
14.4
(69.1)
26. Secondary Outcome
Title Tmax,ss Tiotropium [h]
Description Time from last dosing to maximum concentration of Tiotropium in plasma at steady state (tmax,ss) after 4 weeks of treatment.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 73 78 78 73
Median (Full Range) [hours]
0.133
0.100
0.083
0.133
27. Secondary Outcome
Title AUC(0-3h,ss) Tiotropium [pg*h/mL]
Description Area under the concentration-time curve of Tiotropium at steady state (AUC(0-3h,ss)) from 0 to 3 hours post dosing after 4 weeks of treatment.
Time Frame Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Outcome Measure Data

Analysis Population Description
Evaluable patients.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Measure Participants 58 59 56 50
Geometric Mean (Geometric Coefficient of Variation) [pg*h/mL]
21.8
(42.8)
21.9
(45.3)
21.9
(47.9)
21.0
(42.9)

Adverse Events

Time Frame From first dose up to 21 days after last dose of study medication, upto 86 days.
Adverse Event Reporting Description At each visit, all AEs, regardless of causality, were recorded on the AE e-CRF page after review of the e-Diary and discussion with the patient. Adverse events were recorded on the eCRFs as non-serious or SAEs.
Arm/Group Title 5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Arm/Group Description Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 2 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 1.0 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of FDC of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
All Cause Mortality
5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/90 (2.2%) 3/89 (3.4%) 1/93 (1.1%) 0/88 (0%)
Immune system disorders
Drug Hypersensitivity 1/90 (1.1%) 0/89 (0%) 0/93 (0%) 0/88 (0%)
Infections and infestations
Pneumonia 0/90 (0%) 0/89 (0%) 1/93 (1.1%) 0/88 (0%)
Injury, poisoning and procedural complications
Femur fracture 1/90 (1.1%) 0/89 (0%) 0/93 (0%) 0/88 (0%)
Fibula fracture 1/90 (1.1%) 0/89 (0%) 0/93 (0%) 0/88 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease 1/90 (1.1%) 3/89 (3.4%) 0/93 (0%) 0/88 (0%)
Other (Not Including Serious) Adverse Events
5 µg Tiotropium Tiotropium+Olodaterol 5/2 μg Tiotropium+Olodaterol 5/5 μg Tiotropium+Olodaterol 5/10 μg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/90 (0%) 0/89 (0%) 0/93 (0%) 0/88 (0%)

Limitations/Caveats

Additional secondary endpoints were listed in the original protocol. Those endpoints are of exploratory nature only and were not considered relevant for trial conclusions. For more information see tab "Full Text Review", section "More Information".

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Name/Title Boehringer Ingelheim Call Center
Organization Boehringer Ingelheim
Phone 1-800-243-0127
Email clintriage.rdg@boehringer-ingelheim.com
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00696020
Other Study ID Numbers:
  • 1237.4
  • EudraCT No: 2007-005087-26
First Posted:
Jun 12, 2008
Last Update Posted:
Aug 13, 2015
Last Verified:
Jul 1, 2015