Trial Outcomes & Findings for Characterization of 24 Hour Spirometry Profiles of Inhaled BI 1744 CL and Inhaled Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease (NCT NCT01040689)

NCT ID: NCT01040689

Last Updated: 2014-06-30

Results Overview

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 108 participants
• Primary outcome timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment
• Results posted on: 2014-06-30

Participant Flow

This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments.

Participant milestones

Measure	Placebo / Tio 18mcg / Olo 10mcg / Olo 5mcg Patients were administered placebo in the first period, Tiotropium 18 mcg qd in the second period, Olodaterol 10 mcg qd in the third period and Olodaterol 5 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Olo 5mcg / Olo 10mcg / Tio 18mcg / Placebo Patients were administered Olodaterol 5 mcg qd in the first period, Olodaterol 10 mcg qd in the second period, Tiotropium 18 mcg qd in the third period and placebo in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Olo 10mcg / Placebo / Olo 5mcg / Tio 18mcg Patients were administered Olodaterol 10 mcg qd in the first period, placebo in the second period, Olodaterol 5 mcg qd in the third period and Tiotropium 18 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Tio 18mcg / Olo 5mcg / Placebo / Olo 10mcg Patients were administered Tiotropium 18 mcg qd in the first period, Olodaterol 5 mcg qd in the second period, placebo in the third period and Olodaterol 10 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.
Overall Study STARTED	27	27	27	27
Overall Study COMPLETED	24	25	23	23
Overall Study NOT COMPLETED	3	2	4	4

Reasons for withdrawal

Measure	Placebo / Tio 18mcg / Olo 10mcg / Olo 5mcg Patients were administered placebo in the first period, Tiotropium 18 mcg qd in the second period, Olodaterol 10 mcg qd in the third period and Olodaterol 5 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Olo 5mcg / Olo 10mcg / Tio 18mcg / Placebo Patients were administered Olodaterol 5 mcg qd in the first period, Olodaterol 10 mcg qd in the second period, Tiotropium 18 mcg qd in the third period and placebo in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Olo 10mcg / Placebo / Olo 5mcg / Tio 18mcg Patients were administered Olodaterol 10 mcg qd in the first period, placebo in the second period, Olodaterol 5 mcg qd in the third period and Tiotropium 18 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.	Tio 18mcg / Olo 5mcg / Placebo / Olo 10mcg Patients were administered Tiotropium 18 mcg qd in the first period, Olodaterol 5 mcg qd in the second period, placebo in the third period and Olodaterol 10 mcg qd in the fourth period. Olodaterol was administered via the Respimat inhaler, Tiotropium was administered via the HandiHaler.
Overall Study Adverse Event	0	0	2	4
Overall Study Lack of Efficacy	0	0	1	0
Overall Study Lost to Follow-up	1	0	0	0
Overall Study Withdrawal by Subject	2	1	1	0
Overall Study Other reasons not listed above	0	1	0	0

Baseline Characteristics

Characterization of 24 Hour Spirometry Profiles of Inhaled BI 1744 CL and Inhaled Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease

Baseline characteristics by cohort

Measure	Study Total n=108 Participants Total number of patients treated in the study. This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. 108 patients were assigned randomly to one of 4 treatment sequences in which they received each of 4 treatments, two doses (5 microgram (mcg) or 10 mcg) of Olodaterol (Olo) once daily (qd) delivered via the Respimat inhaler or Tiotropium (Tio) 18 mcg once daily (qd) delivered via the HandiHaler or equivalent placebo. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments.
Age, Continuous	61.7 years STANDARD_DEVIATION 8.8 • n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants
Sex: Female, Male Male	83 Participants n=5 Participants

PRIMARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment

Population: Full analysis set (FAS). FAS is defined as all patients with baseline (pre-dose) data and any evaluable post-dosing data for either co-primary endpoint from the same treatment period. FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment	-0.054 Liter Standard Error 0.020	0.131 Liter Standard Error 0.020	0.152 Liter Standard Error 0.020	0.119 Liter Standard Error 0.020

PRIMARY outcome

Timeframe: 1 h and 10 min prior to am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment	-0.095 Liter Standard Error 0.021	0.036 Liter Standard Error 0.021	0.082 Liter Standard Error 0.021	0.027 Liter Standard Error 0.021

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the first visit of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment	-0.075 Liter Standard Error 0.020	0.083 Liter Standard Error 0.020	0.117 Liter Standard Error 0.020	0.073 Liter Standard Error 0.020

SECONDARY outcome

Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period

Population: FAS including all patients with evaluable data after first dose of treatment.

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.

Outcome measures

Measure	Placebo n=101 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=101 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=100 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=98 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment	-0.021 Liter Standard Error 0.017	0.161 Liter Standard Error 0.017	0.191 Liter Standard Error 0.017	0.111 Liter Standard Error 0.017

SECONDARY outcome

Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the last dose of treatment after six weeks of treatment.

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment	-0.045 Liter Standard Error 0.019	0.161 Liter Standard Error 0.019	0.170 Liter Standard Error 0.019	0.137 Liter Standard Error 0.019

SECONDARY outcome

Timeframe: Study baseline and first day of dosing

Population: FAS including all patients with evaluable data after first dose of treatment.

Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.

Outcome measures

Measure	Placebo n=101 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=101 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=100 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=98 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FEV1 (0-3h) Response	0.040 Liter Standard Error 0.018	0.253 Liter Standard Error 0.018	0.279 Liter Standard Error 0.018	0.201 Liter Standard Error 0.019

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FEV1 (0-3h) Response	0.019 Liter Standard Error 0.022	0.232 Liter Standard Error 0.022	0.253 Liter Standard Error 0.022	0.220 Liter Standard Error 0.022

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of first treatment period. Trough values were the mean of values obtained 23 hours and 23h 50min post the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Trough FEV1 Response	-0.043 Liter Standard Error 0.020	0.090 Liter Standard Error 0.020	0.104 Liter Standard Error 0.020	0.054 Liter Standard Error 0.020

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment.

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response	-0.110 Liter Standard Error 0.038	0.172 Liter Standard Error 0.038	0.192 Liter Standard Error 0.038	0.166 Liter Standard Error 0.038

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response	-0.166 Liter Standard Error 0.039	0.030 Liter Standard Error 0.039	0.086 Liter Standard Error 0.039	0.018 Liter Standard Error 0.039

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment.

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response	-0.138 Liter Standard Error 0.037	0.101 Liter Standard Error 0.037	0.139 Liter Standard Error 0.037	0.091 Liter Standard Error 0.037

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment

Population: FAS including all patients with evaluable data after first dose of treatment.

Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

Outcome measures

Measure	Placebo n=101 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=101 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=100 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=98 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response	-0.024 Liter Standard Error 0.037	0.244 Liter Standard Error 0.037	0.288 Liter Standard Error 0.037	0.191 Liter Standard Error 0.037

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to last dose after six weeks of treatment.

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response	-0.083 Liter Standard Error 0.040	0.234 Liter Standard Error 0.040	0.235 Liter Standard Error 0.040	0.219 Liter Standard Error 0.040

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose in first treatment period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FVC (0-3h) Response	0.086 Liter Standard Error 0.043	0.386 Liter Standard Error 0.043	0.383 Liter Standard Error 0.043	0.381 Liter Standard Error 0.043

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data after six weeks.

Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose in first treatment period. Trough values were mean of the values obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.

Outcome measures

Measure	Placebo n=99 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=100 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=99 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=99 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Trough FVC Response	-0.082 Liter Standard Error 0.041	0.103 Liter Standard Error 0.041	0.130 Liter Standard Error 0.041	0.046 Liter Standard Error 0.041

SECONDARY outcome

Timeframe: 6 weeks

Population: Treated set.

Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations).

Outcome measures

Measure	Placebo n=102 Participants Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg qd n=101 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=101 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=101 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG Palpitations	0.0 percentage of participants	0.0 percentage of participants	1.0 percentage of participants	0.0 percentage of participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG Investigations	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 12 other events

Deaths: 0 deaths

Olo 5 mcg

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Olo 10 mcg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Tiotropium (Tio) 18 mcg qd

Serious events: 5 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=102 participants at risk Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg n=101 participants at risk Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg n=101 participants at risk Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tiotropium (Tio) 18 mcg qd n=101 participants at risk Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Cardiac disorders Angina pectoris	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Cardiac disorders Atrial fibrillation	0.00% 0/102 • 6 weeks	0.99% 1/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Cardiac disorders Cardiac failure	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Immune system disorders Drug hypersensitivity	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Infections and infestations Bronchitis	0.98% 1/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Infections and infestations Diverticulitis	0.98% 1/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Infections and infestations Pneumonia	0.98% 1/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.98% 1/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Reproductive system and breast disorders Balanitis	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks
Reproductive system and breast disorders Benign prostatic hyperplasia	0.98% 1/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/102 • 6 weeks	0.00% 0/101 • 6 weeks	0.00% 0/101 • 6 weeks	0.99% 1/101 • 6 weeks

Other adverse events

Measure	Placebo n=102 participants at risk Matching Placebo delivered by the Respimat Inhaler or Handihaler.	Olo 5 mcg n=101 participants at risk Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg n=101 participants at risk Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tiotropium (Tio) 18 mcg qd n=101 participants at risk Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Infections and infestations Nasopharyngitis	7.8% 8/102 • 6 weeks	5.9% 6/101 • 6 weeks	4.0% 4/101 • 6 weeks	6.9% 7/101 • 6 weeks
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	3.9% 4/102 • 6 weeks	7.9% 8/101 • 6 weeks	2.0% 2/101 • 6 weeks	3.0% 3/101 • 6 weeks

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication
• Publication restrictions are in place

Restriction type: OTHER