Trial Outcomes & Findings for Characterization of 24-hour Lung Function Profiles of Inhaled Tiotropium + Olodaterol Fixed Dose Combination in Patients Suffering From Chronic Obstructive Pulmonary Disease (NCT NCT01559116)

Last Updated: 2015-07-16

Results Overview

Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

219 participants

Primary outcome timeframe

day 1 and week 6

Results posted on

2015-07-16

Participant Flow

This is a randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over design. Each patient was randomised to one of 30 treatment sequences. Each sequence consisted of four 6-week treatment periods separated by 3-week washout periods.

Participant milestones

Participant milestones
Measure	All Subjects Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) \[VIVACITOTM\].
Overall Study STARTED	219
Overall Study COMPLETED	193
Overall Study NOT COMPLETED	26

Reasons for withdrawal

Reasons for withdrawal
Measure	All Subjects Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) \[VIVACITOTM\].
Overall Study Adverse Event	10
Overall Study Lack of Efficacy	1
Overall Study Lost to Follow-up	1
Overall Study Protocol Violation	1
Overall Study Withdrawal by Subject	4
Overall Study other than stated above	9

Baseline Characteristics

Characterization of 24-hour Lung Function Profiles of Inhaled Tiotropium + Olodaterol Fixed Dose Combination in Patients Suffering From Chronic Obstructive Pulmonary Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Subjects n=219 Participants Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) \[VIVACITOTM\].
Age, Continuous	61.1 Years STANDARD_DEVIATION 7.7 • n=5 Participants
Sex: Female, Male Female	90 Participants n=5 Participants
Sex: Female, Male Male	129 Participants n=5 Participants

PRIMARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS): This patient set included patients in the Treated Set (TS) who had any period baseline and any evaluable post-dose data for the primary efficacy endpoint at any Week 6 visits.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.	-0.037 Litres (L) Standard Error 0.014	0.129 Litres (L) Standard Error 0.013	0.117 Litres (L) Standard Error 0.013	0.133 Litres (L) Standard Error 0.014	0.241 Litres (L) Standard Error 0.014	0.244 Litres (L) Standard Error 0.013

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS).

Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
FEV1 AUC0-12h Response [L] After 6 Weeks Treatment.	-0.013 Litres (L) Standard Error 0.015	0.179 Litres (L) Standard Error 0.015	0.171 Litres (L) Standard Error 0.015	0.186 Litres (L) Standard Error 0.015	0.310 Litres (L) Standard Error 0.015	0.305 Litres (L) Standard Error 0.015

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS).

Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
FEV1 AUC12-24h Response [L] After 6 Weeks Treatment.	-0.060 Litres (L) Standard Error 0.014	0.079 Litres (L) Standard Error 0.013	0.062 Litres (L) Standard Error 0.013	0.081 Litres (L) Standard Error 0.014	0.172 Litres (L) Standard Error 0.014	0.182 Litres (L) Standard Error 0.013

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS)

Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Trough FEV1 Response [L] After 6 Weeks Treatment.	-0.006 Litres Standard Error 0.015	0.109 Litres Standard Error 0.015	0.095 Litres Standard Error 0.015	0.122 Litres Standard Error 0.015	0.196 Litres Standard Error 0.015	0.201 Litres Standard Error 0.015

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS).

Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response. The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=135 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=138 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=137 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment.	0.072 Litres (L) Standard Error 0.017	0.291 Litres (L) Standard Error 0.016	0.290 Litres (L) Standard Error 0.016	0.300 Litres (L) Standard Error 0.016	0.422 Litres (L) Standard Error 0.016	0.411 Litres (L) Standard Error 0.016

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS).

Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
FVC AUC0-24h Response [L] After 6 Weeks Treatment.	-0.065 Litres(L) Standard Error 0.023	0.158 Litres(L) Standard Error 0.022	0.172 Litres(L) Standard Error 0.022	0.191 Litres(L) Standard Error 0.022	0.331 Litres(L) Standard Error 0.022	0.368 Litres(L) Standard Error 0.022

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS)

Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
FVC AUC0-12h Response [L] After 6 Weeks Treatment.	-0.023 Litres (L) Standard Error 0.024	0.240 Litres (L) Standard Error 0.024	0.249 Litres (L) Standard Error 0.024	0.261 Litres (L) Standard Error 0.024	0.420 Litres (L) Standard Error 0.024	0.440 Litres (L) Standard Error 0.024

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS).

Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
FVC AUC12-24h Response [L] After 6 Weeks Treatment.	-0.108 Litres (L) Standard Error 0.023	0.077 Litres (L) Standard Error 0.023	0.095 Litres (L) Standard Error 0.023	0.122 Litres (L) Standard Error 0.023	0.243 Litres (L) Standard Error 0.023	0.296 Litres (L) Standard Error 0.023

SECONDARY outcome

Timeframe: day1 and week 6

Population: Full Analysis Set (FAS).

Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Trough FVC Response [L] After 6 Weeks Treatment.	-0.025 Litres (L) Standard Error 0.026	0.134 Litres (L) Standard Error 0.026	0.115 Litres (L) Standard Error 0.026	0.183 Litres (L) Standard Error 0.026	0.282 Litres (L) Standard Error 0.026	0.304 Litres (L) Standard Error 0.026

SECONDARY outcome

Timeframe: day 1 and week 6

Population: Full Analysis Set (FAS)

Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT:2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=136 Participants Olodaterol solution for inhalation - RESPIMAT 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=136 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=135 Participants Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=135 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=138 Participants Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Peak (0-3h) FVC Response [L] After 6 Weeks Treatment.	0.159 Litres (L) Standard Error 0.029	0.463 Litres (L) Standard Error 0.029	0.450 Litres (L) Standard Error 0.029	0.470 Litres (L) Standard Error 0.029	0.612 Litres (L) Standard Error 0.029	0.621 Litres (L) Standard Error 0.028

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 40 other events

Deaths: 0 deaths

Olodaterol (5 µg)

Serious events: 8 serious events

Other events: 21 other events

Deaths: 0 deaths

Tiotropium (2.5 µg)

Serious events: 5 serious events

Other events: 30 other events

Deaths: 0 deaths

Tiotropium (5 µg)

Serious events: 3 serious events

Other events: 29 other events

Deaths: 0 deaths

Tiotropium+Olodaterol FDC (2.5/5 µg)

Serious events: 4 serious events

Other events: 23 other events

Deaths: 0 deaths

Tiotropium+Olodaterol FDC (5/5 µg)

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=138 participants at risk Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=138 participants at risk Olodaterol solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=137 participants at risk Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=138 participants at risk Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=136 participants at risk Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=139 participants at risk Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Cardiac disorders Atrial tachycardia	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Cardiac disorders Coronary artery disease	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Cardiac disorders Myocardial ischaemia	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
General disorders Impaired healing	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
General disorders Inflammation	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Immune system disorders Anaphylactic reaction	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Immune system disorders Food allergy	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Immune system disorders Hypersensitivity	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Infections and infestations Pneumonia	1.4% 2/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Infections and infestations Salpingitis	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Injury, poisoning and procedural complications Comminuted fracture	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Nervous system disorders Cerebrovascular accident	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Nervous system disorders Transient ischaemic attack	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Renal and urinary disorders Renal infarct	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Reproductive system and breast disorders Ovarian cyst	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.4% 2/138 • From drug administration until 21 days after the last administration, upto 92 days.	1.4% 2/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Vascular disorders Arterial disorder	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Vascular disorders Arterial occlusive disease	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	1.4% 2/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Vascular disorders Peripheral artery aneurysm	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.72% 1/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Vascular disorders Peripheral artery thrombosis	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.
Vascular disorders Peripheral vascular disorder	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.73% 1/137 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/136 • From drug administration until 21 days after the last administration, upto 92 days.	0.00% 0/139 • From drug administration until 21 days after the last administration, upto 92 days.

Other adverse events

Other adverse events
Measure	Placebo n=138 participants at risk Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 Oral inhalations once daily in the morning for 6 weeks.	Olodaterol (5 µg) n=138 participants at risk Olodaterol solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (2.5 µg) n=137 participants at risk Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium (5 µg) n=138 participants at risk Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (2.5/5 µg) n=136 participants at risk Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.	Tiotropium+Olodaterol FDC (5/5 µg) n=139 participants at risk Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.
Infections and infestations Nasopharyngitis	10.1% 14/138 • From drug administration until 21 days after the last administration, upto 92 days.	8.7% 12/138 • From drug administration until 21 days after the last administration, upto 92 days.	8.8% 12/137 • From drug administration until 21 days after the last administration, upto 92 days.	8.7% 12/138 • From drug administration until 21 days after the last administration, upto 92 days.	8.8% 12/136 • From drug administration until 21 days after the last administration, upto 92 days.	6.5% 9/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	10.9% 15/138 • From drug administration until 21 days after the last administration, upto 92 days.	3.6% 5/138 • From drug administration until 21 days after the last administration, upto 92 days.	9.5% 13/137 • From drug administration until 21 days after the last administration, upto 92 days.	8.7% 12/138 • From drug administration until 21 days after the last administration, upto 92 days.	5.9% 8/136 • From drug administration until 21 days after the last administration, upto 92 days.	6.5% 9/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Cough	5.1% 7/138 • From drug administration until 21 days after the last administration, upto 92 days.	1.4% 2/138 • From drug administration until 21 days after the last administration, upto 92 days.	2.2% 3/137 • From drug administration until 21 days after the last administration, upto 92 days.	4.3% 6/138 • From drug administration until 21 days after the last administration, upto 92 days.	1.5% 2/136 • From drug administration until 21 days after the last administration, upto 92 days.	5.0% 7/139 • From drug administration until 21 days after the last administration, upto 92 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.5% 9/138 • From drug administration until 21 days after the last administration, upto 92 days.	2.2% 3/138 • From drug administration until 21 days after the last administration, upto 92 days.	2.9% 4/137 • From drug administration until 21 days after the last administration, upto 92 days.	2.2% 3/138 • From drug administration until 21 days after the last administration, upto 92 days.	0.74% 1/136 • From drug administration until 21 days after the last administration, upto 92 days.	1.4% 2/139 • From drug administration until 21 days after the last administration, upto 92 days.

Additional Information

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