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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00696020

Enrollment

360

Registered

2008-06-12

Start date

2008-06-30

Completion date

Unknown

Last updated

2015-08-13

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

Conditions

Pulmonary Disease, Chronic Obstructive

Brief summary

The 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).

Interventions

DRUGBI 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

DRUGtiotropium bromide

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

DEVICERespimat® Inhaler

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

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 3. Male or female patients, 40 years of age or older 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years 5. 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 6. 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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.
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.
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).
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).
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).
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.
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.
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.
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.
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.
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.
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).
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).
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).
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).
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).
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.
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.
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.
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.
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.
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.
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.
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.

Countries

Canada, Germany, United States

Participant flow

Pre-assignment details

A randomised, double-blind, parallel group study. Each patient received their randomised treatment for 28 days.

Participants by arm

Arm	Count
5 µg Tiotropium Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	90
Tiotropium+Olodaterol 5/2 μg 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.	89
Tiotropium+Olodaterol 5/5 μg 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.	93
Tiotropium+Olodaterol 5/10 μg 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.	88
Total	360

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	3	1	2	1
Overall Study	Lack of Efficacy	1	0	0	0
Overall Study	Other not stated above	0	0	1	1
Overall Study	Protocol Violation	0	0	0	1
Overall Study	Withdrawal by Subject	0	1	0	1

Baseline characteristics

Characteristic	5 µg Tiotropium	Tiotropium+Olodaterol 5/2 μg	Tiotropium+Olodaterol 5/5 μg	Tiotropium+Olodaterol 5/10 μg	Total
Age, Continuous	61.87 years STANDARD_DEVIATION 8.5	64.44 years STANDARD_DEVIATION 9.18	64.19 years STANDARD_DEVIATION 9.59	62.66 years STANDARD_DEVIATION 8.86	63.30 years STANDARD_DEVIATION 9.07
Sex: Female, Male Female	47 Participants	33 Participants	45 Participants	39 Participants	164 Participants
Sex: Female, Male Male	43 Participants	56 Participants	48 Participants	49 Participants	196 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 90	0 / 89	0 / 93	0 / 88
serious Total, serious adverse events	2 / 90	3 / 89	1 / 93	0 / 88

Outcome results

Primary

Trough FEV1 Response [L] After 4 Weeks of Treatment

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

Population: 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	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Trough FEV1 Response [L] After 4 Weeks of Treatment	0.110 L	Standard Error 0.021
Tiotropium+Olodaterol 5/2 μg	Trough FEV1 Response [L] After 4 Weeks of Treatment	0.134 L	Standard Error 0.021
Tiotropium+Olodaterol 5/5 μg	Trough FEV1 Response [L] After 4 Weeks of Treatment	0.143 L	Standard Error 0.02
Tiotropium+Olodaterol 5/10 μg	Trough FEV1 Response [L] After 4 Weeks of Treatment	0.168 L	Standard Error 0.021

p-value: 0.379195% CI: [-0.029, 0.076]ANCOVA

p-value: 0.213395% CI: [-0.019, 0.085]ANCOVA

p-value: 0.033795% CI: [0.004, 0.11]ANCOVA

Secondary

AUC(0-1h,ss) Olodaterol [pg*h/mL]

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.

Population: Evaluable patients.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
5 µg Tiotropium	AUC(0-1h,ss) Olodaterol [pg*h/mL]	3.97 pg*h/mL	Geometric Coefficient of Variation 49.4
Tiotropium+Olodaterol 5/2 μg	AUC(0-1h,ss) Olodaterol [pg*h/mL]	5.82 pg*h/mL	Geometric Coefficient of Variation 50.5

Secondary

AUC(0-3h,ss) Tiotropium [pg*h/mL]

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.

Population: Evaluable patients.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
5 µg Tiotropium	AUC(0-3h,ss) Tiotropium [pg*h/mL]	21.8 pg*h/mL	Geometric Coefficient of Variation 42.8
Tiotropium+Olodaterol 5/2 μg	AUC(0-3h,ss) Tiotropium [pg*h/mL]	21.9 pg*h/mL	Geometric Coefficient of Variation 45.3
Tiotropium+Olodaterol 5/5 μg	AUC(0-3h,ss) Tiotropium [pg*h/mL]	21.9 pg*h/mL	Geometric Coefficient of Variation 47.9
Tiotropium+Olodaterol 5/10 μg	AUC(0-3h,ss) Tiotropium [pg*h/mL]	21.0 pg*h/mL	Geometric Coefficient of Variation 42.9

Secondary

Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities

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.

Population: Treated Set.

Arm	Measure	Value (NUMBER)
5 µg Tiotropium	Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities	1 participants
Tiotropium+Olodaterol 5/2 μg	Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities	0 participants
Tiotropium+Olodaterol 5/5 μg	Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities	0 participants
Tiotropium+Olodaterol 5/10 μg	Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities	0 participants

Secondary

Cmax,ss Olodaterol [pg/mL]

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.

Population: 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	Measure	Value (GEOMETRIC_MEAN)	Dispersion
5 µg Tiotropium	Cmax,ss Olodaterol [pg/mL]	4.39 pg/mL	Geometric Coefficient of Variation 49.2
Tiotropium+Olodaterol 5/2 μg	Cmax,ss Olodaterol [pg/mL]	6.87 pg/mL	Geometric Coefficient of Variation 56.1

Secondary

Cmax,ss Tiotropium [pg/mL]

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.

Population: Evaluable patients.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
5 µg Tiotropium	Cmax,ss Tiotropium [pg/mL]	13.3 pg/mL	Geometric Coefficient of Variation 75.3
Tiotropium+Olodaterol 5/2 μg	Cmax,ss Tiotropium [pg/mL]	13.9 pg/mL	Geometric Coefficient of Variation 64.7
Tiotropium+Olodaterol 5/5 μg	Cmax,ss Tiotropium [pg/mL]	12.4 pg/mL	Geometric Coefficient of Variation 69.7
Tiotropium+Olodaterol 5/10 μg	Cmax,ss Tiotropium [pg/mL]	14.4 pg/mL	Geometric Coefficient of Variation 69.1

Secondary

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

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

Population: Full Analysis Set.

Secondary

FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.161 L	Standard Error 0.016
5 µg Tiotropium	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.204 L	Standard Error 0.024
5 µg Tiotropium	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.201 L	Standard Error 0.024
5 µg Tiotropium	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.191 L	Standard Error 0.023
Tiotropium+Olodaterol 5/2 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.289 L	Standard Error 0.024
Tiotropium+Olodaterol 5/2 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.288 L	Standard Error 0.024
Tiotropium+Olodaterol 5/2 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.276 L	Standard Error 0.023
Tiotropium+Olodaterol 5/2 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.201 L	Standard Error 0.016
Tiotropium+Olodaterol 5/5 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.305 L	Standard Error 0.024
Tiotropium+Olodaterol 5/5 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.302 L	Standard Error 0.023
Tiotropium+Olodaterol 5/5 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.270 L	Standard Error 0.022
Tiotropium+Olodaterol 5/5 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.229 L	Standard Error 0.016
Tiotropium+Olodaterol 5/10 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.316 L	Standard Error 0.023
Tiotropium+Olodaterol 5/10 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.315 L	Standard Error 0.024
Tiotropium+Olodaterol 5/10 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.225 L	Standard Error 0.016
Tiotropium+Olodaterol 5/10 μg	FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.309 L	Standard Error 0.025

p-value: 0.005295% CI: [0.026, 0.145]ANCOVA

p-value: 0.008695% CI: [0.02, 0.138]ANCOVA

p-value: <0.000195% CI: [0.066, 0.185]ANCOVA

Secondary

FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment

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)

Population: Full Analysis Set.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.194 L	Standard Error 0.023
Tiotropium+Olodaterol 5/2 μg	FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.282 L	Standard Error 0.023
Tiotropium+Olodaterol 5/5 μg	FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.280 L	Standard Error 0.023
Tiotropium+Olodaterol 5/10 μg	FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.322 L	Standard Error 0.024

p-value: 0.004895% CI: [0.027, 0.149]ANCOVA

p-value: 0.005695% CI: [0.025, 0.146]ANCOVA

p-value: <0.000195% CI: [0.066, 0.189]ANCOVA

Secondary

FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.249 L	Standard Error 0.019
5 µg Tiotropium	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.276 L	Standard Error 0.025
5 µg Tiotropium	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.276 L	Standard Error 0.026
5 µg Tiotropium	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.266 L	Standard Error 0.024
Tiotropium+Olodaterol 5/2 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.359 L	Standard Error 0.025
Tiotropium+Olodaterol 5/2 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.361 L	Standard Error 0.026
Tiotropium+Olodaterol 5/2 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.353 L	Standard Error 0.024
Tiotropium+Olodaterol 5/2 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.284 L	Standard Error 0.019
Tiotropium+Olodaterol 5/5 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.391 L	Standard Error 0.026
Tiotropium+Olodaterol 5/5 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.378 L	Standard Error 0.024
Tiotropium+Olodaterol 5/5 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.348 L	Standard Error 0.024
Tiotropium+Olodaterol 5/5 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.311 L	Standard Error 0.019
Tiotropium+Olodaterol 5/10 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.410 L	Standard Error 0.024
Tiotropium+Olodaterol 5/10 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.397 L	Standard Error 0.025
Tiotropium+Olodaterol 5/10 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.321 L	Standard Error 0.019
Tiotropium+Olodaterol 5/10 μg	FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.386 L	Standard Error 0.027

p-value: 0.007995% CI: [0.023, 0.152]ANCOVA

p-value: 0.01295% CI: [0.018, 0.146]ANCOVA

p-value: <0.000195% CI: [0.08, 0.209]ANCOVA

Secondary

FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	0.143 L	Standard Error 0.031
5 µg Tiotropium	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	0.169 L	Standard Error 0.035
5 µg Tiotropium	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	0.142 L	Standard Error 0.038
5 µg Tiotropium	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	0.145 L	Standard Error 0.034
Tiotropium+Olodaterol 5/2 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	0.203 L	Standard Error 0.035
Tiotropium+Olodaterol 5/2 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	0.197 L	Standard Error 0.038
Tiotropium+Olodaterol 5/2 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	0.189 L	Standard Error 0.034
Tiotropium+Olodaterol 5/2 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	0.181 L	Standard Error 0.031
Tiotropium+Olodaterol 5/5 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	0.205 L	Standard Error 0.038
Tiotropium+Olodaterol 5/5 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	0.219 L	Standard Error 0.035
Tiotropium+Olodaterol 5/5 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	0.193 L	Standard Error 0.034
Tiotropium+Olodaterol 5/5 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	0.209 L	Standard Error 0.031
Tiotropium+Olodaterol 5/10 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	0.180 L	Standard Error 0.035
Tiotropium+Olodaterol 5/10 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	0.172 L	Standard Error 0.036
Tiotropium+Olodaterol 5/10 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	0.175 L	Standard Error 0.032
Tiotropium+Olodaterol 5/10 μg	FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	0.169 L	Standard Error 0.039

p-value: 0.351795% CI: [-0.049, 0.138]ANCOVA

p-value: 0.317195% CI: [-0.046, 0.143]ANCOVA

p-value: 0.465495% CI: [-0.06, 0.13]ANCOVA

Secondary

FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	0.308 L	Standard Error 0.043
5 µg Tiotropium	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	0.310 L	Standard Error 0.042
5 µg Tiotropium	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	0.327 L	Standard Error 0.044
5 µg Tiotropium	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	0.268 L	Standard Error 0.032
Tiotropium+Olodaterol 5/2 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	0.331 L	Standard Error 0.032
Tiotropium+Olodaterol 5/2 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	0.441 L	Standard Error 0.042
Tiotropium+Olodaterol 5/2 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	0.437 L	Standard Error 0.044
Tiotropium+Olodaterol 5/2 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	0.424 L	Standard Error 0.043
Tiotropium+Olodaterol 5/5 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	0.492 L	Standard Error 0.043
Tiotropium+Olodaterol 5/5 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	0.413 L	Standard Error 0.031
Tiotropium+Olodaterol 5/5 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	0.513 L	Standard Error 0.043
Tiotropium+Olodaterol 5/5 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	0.493 L	Standard Error 0.041
Tiotropium+Olodaterol 5/10 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	0.547 L	Standard Error 0.044
Tiotropium+Olodaterol 5/10 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	0.410 L	Standard Error 0.032
Tiotropium+Olodaterol 5/10 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	0.537 L	Standard Error 0.042
Tiotropium+Olodaterol 5/10 μg	FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	0.554 L	Standard Error 0.044

p-value: 0.038495% CI: [0.006, 0.225]ANCOVA

p-value: 0.000995% CI: [0.076, 0.292]ANCOVA

p-value: <0.000195% CI: [0.13, 0.349]ANCOVA

Secondary

FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment

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)

Population: Full Analysis Set.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.309 L	Standard Error 0.044
Tiotropium+Olodaterol 5/2 μg	FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.429 L	Standard Error 0.044
Tiotropium+Olodaterol 5/5 μg	FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.492 L	Standard Error 0.043
Tiotropium+Olodaterol 5/10 μg	FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.547 L	Standard Error 0.044

p-value: 0.033295% CI: [0.01, 0.23]ANCOVA

p-value: 0.001195% CI: [0.074, 0.292]ANCOVA

p-value: <0.000195% CI: [0.128, 0.349]ANCOVA

Secondary

FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.428 L	Standard Error 0.037
5 µg Tiotropium	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.437 L	Standard Error 0.043
5 µg Tiotropium	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.465 L	Standard Error 0.047
5 µg Tiotropium	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.431 L	Standard Error 0.045
Tiotropium+Olodaterol 5/2 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.560 L	Standard Error 0.043
Tiotropium+Olodaterol 5/2 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.586 L	Standard Error 0.047
Tiotropium+Olodaterol 5/2 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.562 L	Standard Error 0.045
Tiotropium+Olodaterol 5/2 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.476 L	Standard Error 0.037
Tiotropium+Olodaterol 5/5 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.648 L	Standard Error 0.046
Tiotropium+Olodaterol 5/5 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.615 L	Standard Error 0.042
Tiotropium+Olodaterol 5/5 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.634 L	Standard Error 0.044
Tiotropium+Olodaterol 5/5 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.576 L	Standard Error 0.036
Tiotropium+Olodaterol 5/10 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	0.696 L	Standard Error 0.046
Tiotropium+Olodaterol 5/10 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	0.690 L	Standard Error 0.043
Tiotropium+Olodaterol 5/10 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	0.583 L	Standard Error 0.037
Tiotropium+Olodaterol 5/10 μg	FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	0.697 L	Standard Error 0.047

p-value: 0.029695% CI: [0.013, 0.249]ANCOVA

p-value: 0.000795% CI: [0.087, 0.32]ANCOVA

p-value: <0.000195% CI: [0.147, 0.383]ANCOVA

Secondary

Patient's Global Rating

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

Population: Full Analysis Set.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Patient's Global Rating	2.866 units on a patient's global rating score	Standard Error 0.112
Tiotropium+Olodaterol 5/2 μg	Patient's Global Rating	2.598 units on a patient's global rating score	Standard Error 0.111
Tiotropium+Olodaterol 5/5 μg	Patient's Global Rating	2.368 units on a patient's global rating score	Standard Error 0.109
Tiotropium+Olodaterol 5/10 μg	Patient's Global Rating	2.377 units on a patient's global rating score	Standard Error 0.113

Secondary

PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	21.973 L/min	Standard Error 3.596
5 µg Tiotropium	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	29.701 L/min	Standard Error 4.966
5 µg Tiotropium	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	32.108 L/min	Standard Error 5.115
5 µg Tiotropium	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	29.734 L/min	Standard Error 4.889
Tiotropium+Olodaterol 5/2 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	52.816 L/min	Standard Error 4.973
Tiotropium+Olodaterol 5/2 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	54.527 L/min	Standard Error 5.13
Tiotropium+Olodaterol 5/2 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	52.091 L/min	Standard Error 4.912
Tiotropium+Olodaterol 5/2 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	35.738 L/min	Standard Error 3.614
Tiotropium+Olodaterol 5/5 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	53.829 L/min	Standard Error 5.022
Tiotropium+Olodaterol 5/5 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	49.722 L/min	Standard Error 4.875
Tiotropium+Olodaterol 5/5 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	48.503 L/min	Standard Error 4.802
Tiotropium+Olodaterol 5/5 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	35.350 L/min	Standard Error 3.533
Tiotropium+Olodaterol 5/10 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 29	56.688 L/min	Standard Error 4.956
Tiotropium+Olodaterol 5/10 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 8	53.448 L/min	Standard Error 5.025
Tiotropium+Olodaterol 5/10 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 1	40.027 L/min	Standard Error 3.646
Tiotropium+Olodaterol 5/10 μg	PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.	Day 15	54.289 L/min	Standard Error 5.18

p-value: 0.00195% CI: [9.057, 35.657]ANCOVA

p-value: 0.005395% CI: [5.613, 31.924]ANCOVA

p-value: <0.000195% CI: [13.565, 40.343]ANCOVA

Secondary

PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment

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)

Population: Full Analysis Set.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment	30.576 L	Standard Error 4.933
Tiotropium+Olodaterol 5/2 μg	PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment	53.443 L	Standard Error 4.956
Tiotropium+Olodaterol 5/5 μg	PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment	50.319 L	Standard Error 4.845
Tiotropium+Olodaterol 5/10 μg	PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment	58.368 L	Standard Error 5.001

p-value: 0.000995% CI: [9.462, 36.272]ANCOVA

p-value: 0.003695% CI: [6.484, 33.002]ANCOVA

p-value: <0.000195% CI: [14.298, 41.287]ANCOVA

Secondary

PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	43.051 L	Standard Error 4.445
5 µg Tiotropium	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	47.819 L	Standard Error 5.213
5 µg Tiotropium	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	48.129 L	Standard Error 6.897
5 µg Tiotropium	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	47.104 L	Standard Error 5.088
Tiotropium+Olodaterol 5/2 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	69.792 L	Standard Error 5.227
Tiotropium+Olodaterol 5/2 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	79.890 L	Standard Error 6.93
Tiotropium+Olodaterol 5/2 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	70.519 L	Standard Error 5.114
Tiotropium+Olodaterol 5/2 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	53.801 L	Standard Error 4.474
Tiotropium+Olodaterol 5/5 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	71.916 L	Standard Error 6.775
Tiotropium+Olodaterol 5/5 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	69.254 L	Standard Error 5.118
Tiotropium+Olodaterol 5/5 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	65.800 L	Standard Error 4.999
Tiotropium+Olodaterol 5/5 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	53.853 L	Standard Error 4.37
Tiotropium+Olodaterol 5/10 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 29	76.461 L	Standard Error 5.159
Tiotropium+Olodaterol 5/10 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 8	73.828 L	Standard Error 5.279
Tiotropium+Olodaterol 5/10 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 1	62.360 L	Standard Error 4.51
Tiotropium+Olodaterol 5/10 μg	PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment	Day 15	73.886 L	Standard Error 6.992

p-value: 0.00195% CI: [9.529, 37.3]ANCOVA

p-value: 0.007895% CI: [4.961, 32.43]ANCOVA

p-value: <0.000195% CI: [15.379, 43.335]ANCOVA

Secondary

PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	29.261 L/min	Standard Error 5.245
5 µg Tiotropium	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	30.139 L/min	Standard Error 5.69
5 µg Tiotropium	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	27.512 L/min	Standard Error 5.68
5 µg Tiotropium	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	28.396 L/min	Standard Error 5.469
Tiotropium+Olodaterol 5/2 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	47.625 L/min	Standard Error 5.643
Tiotropium+Olodaterol 5/2 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	42.179 L/min	Standard Error 5.627
Tiotropium+Olodaterol 5/2 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	41.502 L/min	Standard Error 5.438
Tiotropium+Olodaterol 5/2 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	41.838 L/min	Standard Error 5.197
Tiotropium+Olodaterol 5/5 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	52.249 L/min	Standard Error 5.688
Tiotropium+Olodaterol 5/5 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	48.503 L/min	Standard Error 5.704
Tiotropium+Olodaterol 5/5 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	48.212 L/min	Standard Error 5.497
Tiotropium+Olodaterol 5/5 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	45.179 L/min	Standard Error 5.253
Tiotropium+Olodaterol 5/10 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 29	47.289 L/min	Standard Error 5.606
Tiotropium+Olodaterol 5/10 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 8	47.924 L/min	Standard Error 5.819
Tiotropium+Olodaterol 5/10 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 1	41.852 L/min	Standard Error 5.36
Tiotropium+Olodaterol 5/10 μg	PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment	Day 15	45.798 L/min	Standard Error 5.803

p-value: 0.089995% CI: [-2.055, 28.267]ANCOVA

p-value: 0.011195% CI: [4.549, 35.084]ANCOVA

p-value: 0.016695% CI: [3.458, 34.329]ANCOVA

Secondary

Physician's Global Evaluation

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Physician's Global Evaluation	Day 8	5.139 units on a scale	Standard Error 0.102
5 µg Tiotropium	Physician's Global Evaluation	Day 29	5.264 units on a scale	Standard Error 0.115
5 µg Tiotropium	Physician's Global Evaluation	Day 15	5.272 units on a scale	Standard Error 0.113
Tiotropium+Olodaterol 5/2 μg	Physician's Global Evaluation	Day 8	5.102 units on a scale	Standard Error 0.102
Tiotropium+Olodaterol 5/2 μg	Physician's Global Evaluation	Day 29	5.295 units on a scale	Standard Error 0.115
Tiotropium+Olodaterol 5/2 μg	Physician's Global Evaluation	Day 15	5.130 units on a scale	Standard Error 0.113
Tiotropium+Olodaterol 5/5 μg	Physician's Global Evaluation	Day 15	5.382 units on a scale	Standard Error 0.111
Tiotropium+Olodaterol 5/5 μg	Physician's Global Evaluation	Day 8	5.185 units on a scale	Standard Error 0.1
Tiotropium+Olodaterol 5/5 μg	Physician's Global Evaluation	Day 29	5.447 units on a scale	Standard Error 0.113
Tiotropium+Olodaterol 5/10 μg	Physician's Global Evaluation	Day 8	5.149 units on a scale	Standard Error 0.102
Tiotropium+Olodaterol 5/10 μg	Physician's Global Evaluation	Day 29	5.252 units on a scale	Standard Error 0.115
Tiotropium+Olodaterol 5/10 μg	Physician's Global Evaluation	Day 15	5.104 units on a scale	Standard Error 0.113

Secondary

Tmax,ss Olodaterol [h]

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.

Population: Evaluable patients.

Arm	Measure	Value (MEDIAN)
5 µg Tiotropium	Tmax,ss Olodaterol [h]	0.167 hours
Tiotropium+Olodaterol 5/2 μg	Tmax,ss Olodaterol [h]	0.183 hours

Secondary

Tmax,ss Tiotropium [h]

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.

Population: Evaluable patients.

Arm	Measure	Value (MEDIAN)
5 µg Tiotropium	Tmax,ss Tiotropium [h]	0.133 hours
Tiotropium+Olodaterol 5/2 μg	Tmax,ss Tiotropium [h]	0.100 hours
Tiotropium+Olodaterol 5/5 μg	Tmax,ss Tiotropium [h]	0.083 hours
Tiotropium+Olodaterol 5/10 μg	Tmax,ss Tiotropium [h]	0.133 hours

Secondary

Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 8	0.093 L	Standard Error 0.02
5 µg Tiotropium	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 15	0.099 L	Standard Error 0.02
Tiotropium+Olodaterol 5/2 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 15	0.141 L	Standard Error 0.02
Tiotropium+Olodaterol 5/2 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 8	0.149 L	Standard Error 0.02
Tiotropium+Olodaterol 5/5 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 8	0.154 L	Standard Error 0.019
Tiotropium+Olodaterol 5/5 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 15	0.159 L	Standard Error 0.02
Tiotropium+Olodaterol 5/10 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 8	0.166 L	Standard Error 0.02
Tiotropium+Olodaterol 5/10 μg	Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.	Day 15	0.154 L	Standard Error 0.021

p-value: 0.116395% CI: [-0.01, 0.093]ANCOVA

p-value: 0.022495% CI: [0.009, 0.111]ANCOVA

p-value: 0.03895% CI: [0.003, 0.107]ANCOVA

Secondary

Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 29	0.189 L	Standard Error 0.036
5 µg Tiotropium	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 8	0.156 L	Standard Error 0.033
5 µg Tiotropium	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 15	0.171 L	Standard Error 0.034
Tiotropium+Olodaterol 5/2 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 15	0.196 L	Standard Error 0.034
Tiotropium+Olodaterol 5/2 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 8	0.215 L	Standard Error 0.033
Tiotropium+Olodaterol 5/2 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 29	0.191 L	Standard Error 0.036
Tiotropium+Olodaterol 5/5 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 15	0.280 L	Standard Error 0.033
Tiotropium+Olodaterol 5/5 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 8	0.265 L	Standard Error 0.032
Tiotropium+Olodaterol 5/5 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 29	0.288 L	Standard Error 0.036
Tiotropium+Olodaterol 5/10 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 8	0.275 L	Standard Error 0.033
Tiotropium+Olodaterol 5/10 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 29	0.306 L	Standard Error 0.037
Tiotropium+Olodaterol 5/10 μg	Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment	Day 15	0.285 L	Standard Error 0.034

p-value: 0.957395% CI: [-0.089, 0.094]ANCOVA

p-value: 0.032195% CI: [0.009, 0.189]ANCOVA

p-value: 0.012595% CI: [0.025, 0.209]ANCOVA

Secondary

Weekly Mean Evening PEF [L/Min]

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (MEAN)	Dispersion
5 µg Tiotropium	Weekly Mean Evening PEF [L/Min]	Week 1	249.10 L/min	Standard Error 3.419
5 µg Tiotropium	Weekly Mean Evening PEF [L/Min]	Week 2	247.10 L/min	Standard Error 3.804
5 µg Tiotropium	Weekly Mean Evening PEF [L/Min]	Week 3	249.78 L/min	Standard Error 3.765
5 µg Tiotropium	Weekly Mean Evening PEF [L/Min]	Week 4	246.77 L/min	Standard Error 3.777
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Evening PEF [L/Min]	Week 2	260.73 L/min	Standard Error 3.814
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Evening PEF [L/Min]	Week 3	258.20 L/min	Standard Error 3.791
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Evening PEF [L/Min]	Week 4	253.12 L/min	Standard Error 3.803
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Evening PEF [L/Min]	Week 1	260.86 L/min	Standard Error 3.425
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Evening PEF [L/Min]	Week 3	268.16 L/min	Standard Error 3.702
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Evening PEF [L/Min]	Week 2	267.31 L/min	Standard Error 3.738
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Evening PEF [L/Min]	Week 4	266.61 L/min	Standard Error 3.714
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Evening PEF [L/Min]	Week 1	267.47 L/min	Standard Error 3.36
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Evening PEF [L/Min]	Week 4	265.50 L/min	Standard Error 3.896
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Evening PEF [L/Min]	Week 2	266.40 L/min	Standard Error 3.909
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Evening PEF [L/Min]	Week 1	268.58 L/min	Standard Error 3.51
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Evening PEF [L/Min]	Week 3	265.67 L/min	Standard Error 3.884

Secondary

Weekly Mean Number of Occasions of Rescue Therapy Used Per Day

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 1	1.905 occasion(s)	Standard Error 0.155
5 µg Tiotropium	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 2	1.784 occasion(s)	Standard Error 0.178
5 µg Tiotropium	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 3	1.947 occasion(s)	Standard Error 0.183
5 µg Tiotropium	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 4	2.017 occasion(s)	Standard Error 0.172
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 2	1.610 occasion(s)	Standard Error 0.177
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 3	1.650 occasion(s)	Standard Error 0.182
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 4	1.615 occasion(s)	Standard Error 0.172
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 1	1.512 occasion(s)	Standard Error 0.155
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 3	1.492 occasion(s)	Standard Error 0.18
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 2	1.476 occasion(s)	Standard Error 0.175
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 4	1.602 occasion(s)	Standard Error 0.169
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 1	1.504 occasion(s)	Standard Error 0.152
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 4	1.482 occasion(s)	Standard Error 0.176
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 2	1.477 occasion(s)	Standard Error 0.182
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 1	1.669 occasion(s)	Standard Error 0.159
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Number of Occasions of Rescue Therapy Used Per Day	Week 3	1.563 occasion(s)	Standard Error 0.187

Secondary

Weekly Mean Pre-dose Morning PEF [L/Min]

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

Population: Full Analysis Set.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
5 µg Tiotropium	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 1	227.81 L/min	Standard Error 3.198
5 µg Tiotropium	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 2	228.57 L/min	Standard Error 3.401
5 µg Tiotropium	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 3	228.82 L/min	Standard Error 3.663
5 µg Tiotropium	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 4	226.49 L/min	Standard Error 3.678
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 2	240.87 L/min	Standard Error 3.415
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 3	239.61 L/min	Standard Error 3.684
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 4	234.14 L/min	Standard Error 3.699
Tiotropium+Olodaterol 5/2 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 1	244.43 L/min	Standard Error 3.208
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 3	249.39 L/min	Standard Error 3.639
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 2	249.99 L/min	Standard Error 3.377
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 4	249.17 L/min	Standard Error 3.654
Tiotropium+Olodaterol 5/5 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 1	248.84 L/min	Standard Error 3.174
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 4	247.30 L/min	Standard Error 3.816
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 2	247.77 L/min	Standard Error 3.524
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 1	248.76 L/min	Standard Error 3.31
Tiotropium+Olodaterol 5/10 μg	Weekly Mean Pre-dose Morning PEF [L/Min]	Week 3	248.33 L/min	Standard Error 3.8

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

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

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Trough FEV1 Response [L] After 4 Weeks of Treatment

AUC(0-1h,ss) Olodaterol [pg*h/mL]

AUC(0-3h,ss) Tiotropium [pg*h/mL]

Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities

Cmax,ss Olodaterol [pg/mL]

Cmax,ss Tiotropium [pg/mL]

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

FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment

FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment

FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.

FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment

FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

Patient's Global Rating

PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.

PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment

PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment

PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment

Physician's Global Evaluation

Tmax,ss Olodaterol [h]

Tmax,ss Tiotropium [h]

Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment.

Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment

Weekly Mean Evening PEF [L/Min]

Weekly Mean Number of Occasions of Rescue Therapy Used Per Day

Weekly Mean Pre-dose Morning PEF [L/Min]