Trial Outcomes & Findings for Combination of Orally Inhaled BI1744CL/Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease ( COPD) (NCT NCT00696020)

NCT ID: NCT00696020

Last Updated: 2015-08-13

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 360 participants
• Primary outcome timeframe: Baseline and 4 weeks
• Results posted on: 2015-08-13

Participant Flow

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

Participant milestones

Measure	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.	Tiotropium+Olodaterol 5/2 μg 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.	Tiotropium+Olodaterol 5/5 μg 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.	Tiotropium+Olodaterol 5/10 μg 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.
Overall Study STARTED	90	89	93	88
Overall Study COMPLETED	86	87	90	84
Overall Study NOT COMPLETED	4	2	3	4

Reasons for withdrawal

Measure	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.	Tiotropium+Olodaterol 5/2 μg 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.	Tiotropium+Olodaterol 5/5 μg 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.	Tiotropium+Olodaterol 5/10 μg 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.
Overall Study Adverse Event	3	1	2	1
Overall Study Lack of Efficacy	1	0	0	0
Overall Study Protocol Violation	0	0	0	1
Overall Study Withdrawal by Subject	0	1	0	1
Overall Study Other not stated above	0	0	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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 n=360 Participants Total of all reporting groups
Age, Continuous	61.87 years STANDARD_DEVIATION 8.50 • n=5 Participants	64.44 years STANDARD_DEVIATION 9.18 • n=7 Participants	64.19 years STANDARD_DEVIATION 9.59 • n=5 Participants	62.66 years STANDARD_DEVIATION 8.86 • n=4 Participants	63.30 years STANDARD_DEVIATION 9.07 • n=21 Participants
Sex: Female, Male Female	47 Participants n=5 Participants	33 Participants n=7 Participants	45 Participants n=5 Participants	39 Participants n=4 Participants	164 Participants n=21 Participants
Sex: Female, Male Male	43 Participants n=5 Participants	56 Participants n=7 Participants	48 Participants n=5 Participants	49 Participants n=4 Participants	196 Participants n=21 Participants

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
Trough FEV1 Response [L] After 4 Weeks of Treatment	0.110 L Standard Error 0.021	0.134 L Standard Error 0.021	0.143 L Standard Error 0.020	0.168 L Standard Error 0.021

SECONDARY outcome

Timeframe: Baseline, 1 week and 2 weeks

Population: Full Analysis Set.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment. Day 8	0.093 L Standard Error 0.020	0.149 L Standard Error 0.020	0.154 L Standard Error 0.019	0.166 L Standard Error 0.020
Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment. Day 15	0.099 L Standard Error 0.020	0.141 L Standard Error 0.020	0.159 L Standard Error 0.020	0.154 L Standard Error 0.021

SECONDARY outcome

Timeframe: Baseline, 1 week, 2 weeks and 4 weeks

Population: Full Analysis Set.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment Day 8	0.156 L Standard Error 0.033	0.215 L Standard Error 0.033	0.265 L Standard Error 0.032	0.275 L Standard Error 0.033
Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment Day 15	0.171 L Standard Error 0.034	0.196 L Standard Error 0.034	0.280 L Standard Error 0.033	0.285 L Standard Error 0.034
Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment Day 29	0.189 L Standard Error 0.036	0.191 L Standard Error 0.036	0.288 L Standard Error 0.036	0.306 L Standard Error 0.037

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	0.201 L Standard Error 0.016	0.229 L Standard Error 0.016	0.225 L Standard Error 0.016
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	0.289 L Standard Error 0.024	0.302 L Standard Error 0.023	0.315 L Standard Error 0.024
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	0.288 L Standard Error 0.024	0.305 L Standard Error 0.024	0.309 L Standard Error 0.025
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	0.276 L Standard Error 0.023	0.270 L Standard Error 0.022	0.316 L Standard Error 0.023

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	0.331 L Standard Error 0.032	0.413 L Standard Error 0.031	0.410 L Standard Error 0.032
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	0.441 L Standard Error 0.042	0.493 L Standard Error 0.041	0.537 L Standard Error 0.042
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	0.437 L Standard Error 0.044	0.513 L Standard Error 0.043	0.554 L Standard Error 0.044
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	0.424 L Standard Error 0.043	0.492 L Standard Error 0.043	0.547 L Standard Error 0.044

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	35.738 L/min Standard Error 3.614	35.350 L/min Standard Error 3.533	40.027 L/min Standard Error 3.646
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	52.816 L/min Standard Error 4.973	49.722 L/min Standard Error 4.875	53.448 L/min Standard Error 5.025
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	54.527 L/min Standard Error 5.130	53.829 L/min Standard Error 5.022	54.289 L/min Standard Error 5.180
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	52.091 L/min Standard Error 4.912	48.503 L/min Standard Error 4.802	56.688 L/min Standard Error 4.956

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.194 L Standard Error 0.023	0.282 L Standard Error 0.023	0.280 L Standard Error 0.023	0.322 L Standard Error 0.024

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment	0.309 L Standard Error 0.044	0.429 L Standard Error 0.044	0.492 L Standard Error 0.043	0.547 L Standard Error 0.044

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment	30.576 L Standard Error 4.933	53.443 L Standard Error 4.956	50.319 L Standard Error 4.845	58.368 L Standard Error 5.001

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	0.284 L Standard Error 0.019	0.311 L Standard Error 0.019	0.321 L Standard Error 0.019
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	0.359 L Standard Error 0.025	0.378 L Standard Error 0.024	0.397 L Standard Error 0.025
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	0.361 L Standard Error 0.026	0.391 L Standard Error 0.026	0.386 L Standard Error 0.027
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	0.353 L Standard Error 0.024	0.348 L Standard Error 0.024	0.410 L Standard Error 0.024

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	0.476 L Standard Error 0.037	0.576 L Standard Error 0.036	0.583 L Standard Error 0.037
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	0.560 L Standard Error 0.043	0.615 L Standard Error 0.042	0.690 L Standard Error 0.043
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	0.586 L Standard Error 0.047	0.648 L Standard Error 0.046	0.697 L Standard Error 0.047
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	0.562 L Standard Error 0.045	0.634 L Standard Error 0.044	0.696 L Standard Error 0.046

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
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	53.801 L Standard Error 4.474	53.853 L Standard Error 4.370	62.360 L Standard Error 4.510
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	69.792 L Standard Error 5.227	69.254 L Standard Error 5.118	73.828 L Standard Error 5.279
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	79.890 L Standard Error 6.930	71.916 L Standard Error 6.775	73.886 L Standard Error 6.992
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	70.519 L Standard Error 5.114	65.800 L Standard Error 4.999	76.461 L Standard Error 5.159

SECONDARY outcome

Timeframe: After first administration, 1 week, 2 weeks and 4 weeks

Population: Full Analysis Set.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Population: Full Analysis Set.

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.

Outcome measures

Measure	5 µg Tiotropium n=87 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=88 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=86 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=83 Participants 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.
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	0.181 L Standard Error 0.031	0.209 L Standard Error 0.031	0.175 L Standard Error 0.032
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	0.203 L Standard Error 0.035	0.219 L Standard Error 0.035	0.172 L Standard Error 0.036
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	0.197 L Standard Error 0.038	0.205 L Standard Error 0.038	0.169 L Standard Error 0.039
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	0.189 L Standard Error 0.034	0.193 L Standard Error 0.034	0.180 L Standard Error 0.035

SECONDARY outcome

Timeframe: 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks

Population: Full Analysis Set.

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.

Outcome measures

Measure	5 µg Tiotropium n=87 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=88 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=86 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=83 Participants 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.
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	41.838 L/min Standard Error 5.197	45.179 L/min Standard Error 5.253	41.852 L/min Standard Error 5.360
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 5.690	47.625 L/min Standard Error 5.643	48.503 L/min Standard Error 5.704	47.924 L/min Standard Error 5.819
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 5.680	42.179 L/min Standard Error 5.627	52.249 L/min Standard Error 5.688	45.798 L/min Standard Error 5.803
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	41.502 L/min Standard Error 5.438	48.212 L/min Standard Error 5.497	47.289 L/min Standard Error 5.606

SECONDARY outcome

Timeframe: Throughout the 4 week treatment period

Population: Full Analysis Set.

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).

Outcome measures

Measure	5 µg Tiotropium n=89 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=88 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=90 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=83 Participants 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.
Weekly Mean Pre-dose Morning PEF [L/Min] Week 1	227.81 L/min Standard Error 3.198	244.43 L/min Standard Error 3.208	248.84 L/min Standard Error 3.174	248.76 L/min Standard Error 3.310
Weekly Mean Pre-dose Morning PEF [L/Min] Week 2	228.57 L/min Standard Error 3.401	240.87 L/min Standard Error 3.415	249.99 L/min Standard Error 3.377	247.77 L/min Standard Error 3.524
Weekly Mean Pre-dose Morning PEF [L/Min] Week 3	228.82 L/min Standard Error 3.663	239.61 L/min Standard Error 3.684	249.39 L/min Standard Error 3.639	248.33 L/min Standard Error 3.800
Weekly Mean Pre-dose Morning PEF [L/Min] Week 4	226.49 L/min Standard Error 3.678	234.14 L/min Standard Error 3.699	249.17 L/min Standard Error 3.654	247.30 L/min Standard Error 3.816

SECONDARY outcome

Timeframe: Throughout the 4 weeks treatment period

Population: Full Analysis Set.

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).

Outcome measures

Measure	5 µg Tiotropium n=89 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=88 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=92 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=84 Participants 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.
Weekly Mean Evening PEF [L/Min] Week 1	249.10 L/min Standard Error 3.419	260.86 L/min Standard Error 3.425	267.47 L/min Standard Error 3.360	268.58 L/min Standard Error 3.510
Weekly Mean Evening PEF [L/Min] Week 2	247.10 L/min Standard Error 3.804	260.73 L/min Standard Error 3.814	267.31 L/min Standard Error 3.738	266.40 L/min Standard Error 3.909
Weekly Mean Evening PEF [L/Min] Week 3	249.78 L/min Standard Error 3.765	258.20 L/min Standard Error 3.791	268.16 L/min Standard Error 3.702	265.67 L/min Standard Error 3.884
Weekly Mean Evening PEF [L/Min] Week 4	246.77 L/min Standard Error 3.777	253.12 L/min Standard Error 3.803	266.61 L/min Standard Error 3.714	265.50 L/min Standard Error 3.896

SECONDARY outcome

Timeframe: Throughout the 4 weeks treatment period

Population: Full Analysis Set.

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

Outcome measures

Measure	5 µg Tiotropium n=89 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=92 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=84 Participants 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.
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day Week 1	1.905 occasion(s) Standard Error 0.155	1.512 occasion(s) Standard Error 0.155	1.504 occasion(s) Standard Error 0.152	1.669 occasion(s) Standard Error 0.159
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day Week 2	1.784 occasion(s) Standard Error 0.178	1.610 occasion(s) Standard Error 0.177	1.476 occasion(s) Standard Error 0.175	1.477 occasion(s) Standard Error 0.182
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day Week 3	1.947 occasion(s) Standard Error 0.183	1.650 occasion(s) Standard Error 0.182	1.492 occasion(s) Standard Error 0.180	1.563 occasion(s) Standard Error 0.187
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day Week 4	2.017 occasion(s) Standard Error 0.172	1.615 occasion(s) Standard Error 0.172	1.602 occasion(s) Standard Error 0.169	1.482 occasion(s) Standard Error 0.176

SECONDARY outcome

Timeframe: 1 week, 2 weeks and 4 weeks

Population: Full Analysis Set.

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).

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=92 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
Physician's Global Evaluation Day 8	5.139 units on a scale Standard Error 0.102	5.102 units on a scale Standard Error 0.102	5.185 units on a scale Standard Error 0.100	5.149 units on a scale Standard Error 0.102
Physician's Global Evaluation Day 15	5.272 units on a scale Standard Error 0.113	5.130 units on a scale Standard Error 0.113	5.382 units on a scale Standard Error 0.111	5.104 units on a scale Standard Error 0.113
Physician's Global Evaluation Day 29	5.264 units on a scale Standard Error 0.115	5.295 units on a scale Standard Error 0.115	5.447 units on a scale Standard Error 0.113	5.252 units on a scale Standard Error 0.115

SECONDARY outcome

Timeframe: 4 weeks

Population: Full Analysis Set.

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).

Outcome measures

Measure	5 µg Tiotropium n=86 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=87 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=90 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=84 Participants 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.
Patient's Global Rating	2.866 units on a patient's global rating score Standard Error 0.112	2.598 units on a patient's global rating score Standard Error 0.111	2.368 units on a patient's global rating score Standard Error 0.109	2.377 units on a patient's global rating score Standard Error 0.113

SECONDARY outcome

Timeframe: From first dose up to 21 days after last dose of study medication.

Population: Treated Set.

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.

Outcome measures

Measure	5 µg Tiotropium n=90 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=93 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=88 Participants 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.
Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities	1 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	5 µg Tiotropium n=42 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=59 Participants 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.	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.	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.
Cmax,ss Olodaterol [pg/mL]	4.39 pg/mL Geometric Coefficient of Variation 49.2	6.87 pg/mL Geometric Coefficient of Variation 56.1	—	—

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Population: Evaluable patients.

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.

Outcome measures

Measure	5 µg Tiotropium n=42 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=59 Participants 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.	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.	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.
Tmax,ss Olodaterol [h]	0.167 hours Interval 0.083 to 0.917	0.183 hours Interval 0.067 to 1.07	—	—

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Population: Evaluable patients.

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.

Outcome measures

Measure	5 µg Tiotropium n=28 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=52 Participants 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.	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.	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.
AUC(0-1h,ss) Olodaterol [pg*h/mL]	3.97 pg*h/mL Geometric Coefficient of Variation 49.4	5.82 pg*h/mL Geometric Coefficient of Variation 50.5	—	—

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Population: Evaluable patients.

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

Outcome measures

Measure	5 µg Tiotropium n=78 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=78 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=73 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=73 Participants 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.
Cmax,ss Tiotropium [pg/mL]	13.3 pg/mL Geometric Coefficient of Variation 75.3	13.9 pg/mL Geometric Coefficient of Variation 64.7	12.4 pg/mL Geometric Coefficient of Variation 69.7	14.4 pg/mL Geometric Coefficient of Variation 69.1

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Population: Evaluable patients.

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

Outcome measures

Measure	5 µg Tiotropium n=73 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=78 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=78 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=73 Participants 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.
Tmax,ss Tiotropium [h]	0.133 hours Interval 0.05 to 1.0	0.100 hours Interval 0.017 to 0.983	0.083 hours Interval 0.067 to 0.917	0.133 hours Interval 0.05 to 1.0

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.

Population: Evaluable patients.

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.

Outcome measures

Measure	5 µg Tiotropium n=58 Participants Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=59 Participants 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.	Tiotropium+Olodaterol 5/5 μg n=56 Participants 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.	Tiotropium+Olodaterol 5/10 μg n=50 Participants 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.
AUC(0-3h,ss) Tiotropium [pg*h/mL]	21.8 pg*h/mL Geometric Coefficient of Variation 42.8	21.9 pg*h/mL Geometric Coefficient of Variation 45.3	21.9 pg*h/mL Geometric Coefficient of Variation 47.9	21.0 pg*h/mL Geometric Coefficient of Variation 42.9

Adverse Events

5 µg Tiotropium

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

Tiotropium+Olodaterol 5/2 μg

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

Tiotropium+Olodaterol 5/5 μg

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Tiotropium+Olodaterol 5/10 μg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	5 µg Tiotropium n=90 participants at risk Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.	Tiotropium+Olodaterol 5/2 μg n=89 participants at risk 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.	Tiotropium+Olodaterol 5/5 μg n=93 participants at risk 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.	Tiotropium+Olodaterol 5/10 μg n=88 participants at risk 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.
Infections and infestations Pneumonia	0.00% 0/90 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/89 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	1.1% 1/93 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/88 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.
Immune system disorders Drug Hypersensitivity	1.1% 1/90 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/89 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/93 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/88 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.1% 1/90 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	3.4% 3/89 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/93 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/88 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.
Injury, poisoning and procedural complications Femur fracture	1.1% 1/90 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/89 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/93 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/88 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.
Injury, poisoning and procedural complications Fibula fracture	1.1% 1/90 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/89 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/93 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.	0.00% 0/88 • From first dose up to 21 days after last dose of study medication, upto 86 days. 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.

Other adverse events

Adverse event data not reported

Additional Information

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Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
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