Trial Outcomes & Findings for A Randomized, Double-Blind, 4-way Crossover Study to Evaluate the Efficacy of of 24 Hour Spirometry Profiles of Inhaled BI 1744 CL and Inhaled Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease (NCT NCT01040728)

NCT ID: NCT01040728

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 first 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: 122 participants
• Primary outcome timeframe: 1 hour (h) and 10 minutes (min) prior to the 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	31	30	31	30
Overall Study COMPLETED	27	19	30	24
Overall Study NOT COMPLETED	4	11	1	6

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	4	8	0	4
Overall Study Withdrawal by Subject	0	1	1	0
Overall Study Protocol Violation	0	0	0	1
Overall Study Lack of Efficacy	0	1	0	1
Overall Study Other reasons not listed above	0	1	0	0

Baseline Characteristics

A Randomized, Double-Blind, 4-way Crossover Study to Evaluate the Efficacy of 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=122 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. 122 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	62.7 years STANDARD_DEVIATION 7.9 • n=5 Participants
Sex: Female, Male Female	47 Participants n=5 Participants
Sex: Female, Male Male	75 Participants n=5 Participants

PRIMARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to the 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 of the co-primary endpoints. FAS including all patients with evaluable data for this endpoint 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 first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 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	-0.008 Liter Standard Error 0.019	0.189 Liter Standard Error 0.019	0.213 Liter Standard Error 0.019	0.213 Liter Standard Error 0.019

PRIMARY outcome

Timeframe: 1 h and 10 min prior to the 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 for this endpoint 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 first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 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	-0.059 Liter Standard Error 0.018	0.094 Liter Standard Error 0.018	0.111 Liter Standard Error 0.018	0.105 Liter Standard Error 0.018

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 for this endpoint 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 at the first randomized treatment visit for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 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	-0.033 Liter Standard Error 0.019	0.142 Liter Standard Error 0.018	0.158 Liter Standard Error 0.018	0.159 Liter Standard Error 0.018

SECONDARY outcome

Timeframe: 1 hour (h) prior and 10 minutes (min) prior to the am 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 the first dose of treatment period

Population: FAS including all patients with evaluable data for this endpoint 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 treatment at the first treatment visit for the first 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=107 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=113 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=113 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=111 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	0.018 Liter Standard Error 0.018	0.232 Liter Standard Error 0.017	0.256 Liter Standard Error 0.017	0.169 Liter Standard Error 0.018

SECONDARY outcome

Timeframe: 1 hour (h) prior and 10 minutes (min) prior to the am 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 the first dose of treatment after six weeks of treatment

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 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	0.011 Liter Standard Error 0.020	0.225 Liter Standard Error 0.019	0.255 Liter Standard Error 0.020	0.246 Liter Standard Error 0.019

SECONDARY outcome

Timeframe: Study baseline and first day of dosing

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first 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=107 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=113 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=113 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=111 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FEV1 (0-3h) Response	0.076 Liter Standard Error 0.019	0.313 Liter Standard Error 0.019	0.342 Liter Standard Error 0.019	0.251 Liter Standard Error 0.019

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FEV1 (0-3h) Response	0.082 Liter Standard Error 0.020	0.290 Liter Standard Error 0.020	0.325 Liter Standard Error 0.020	0.325 Liter Standard Error 0.020

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first period. Trough values were the mean of values obtained 23h 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Trough FEV1 Response	0.003 Liter Standard Error 0.019	0.137 Liter Standard Error 0.019	0.146 Liter Standard Error 0.019	0.161 Liter Standard Error 0.019

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to the am 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 for this endpoint 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 treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 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	-0.006 Liter Standard Error 0.035	0.324 Liter Standard Error 0.034	0.321 Liter Standard Error 0.035	0.364 Liter Standard Error 0.035

SECONDARY outcome

Timeframe: 1 h and 10 min prior to the 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 last dose after six weeks of treatment

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response	-0.109 Liter Standard Error 0.036	0.169 Liter Standard Error 0.035	0.155 Liter Standard Error 0.036	0.192 Liter Standard Error 0.035

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 last dose after six weeks of treatment

Population: FAS including all patients with evaluable data for this endpoint 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 treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response	-0.057 Liter Standard Error 0.036	0.247 Liter Standard Error 0.035	0.226 Liter Standard Error 0.036	0.278 Liter Standard Error 0.035

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to the am 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 first dose of treatment

Population: FAS including all patients with evaluable data for this endpoint 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 of treatment for the first 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=107 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=113 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=113 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=111 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response	0.053 Liter Standard Error 0.035	0.423 Liter Standard Error 0.034	0.419 Liter Standard Error 0.034	0.316 Liter Standard Error 0.034

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to the am 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 of treatment after six weeks of treatment

Population: FAS including all patients with evaluable data for this endpoint 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 of treatment for the first 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response	0.044 Liter Standard Error 0.035	0.388 Liter Standard Error 0.034	0.397 Liter Standard Error 0.035	0.414 Liter Standard Error 0.034

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data for this endpoint 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 of treatment for the first period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last am 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=106 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Peak FVC (0-3h) Response	0.191 Liter Standard Error 0.037	0.526 Liter Standard Error 0.036	0.537 Liter Standard Error 0.037	0.569 Liter Standard Error 0.037

SECONDARY outcome

Timeframe: Study baseline and 6 weeks

Population: FAS including all patients with evaluable data for this endpoint 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 of treatment for the first period. Trough values were the mean of 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=105 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=107 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=112 Participants Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Trough FVC Response	-0.001 Liter Standard Error 0.037	0.243 Liter Standard Error 0.036	0.215 Liter Standard Error 0.037	0.255 Liter Standard Error 0.037

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=109 Participants Matching Placebo delivered by the Respimat Inhaler or Aerolizer Inhaler.	Olo 5 mcg qd n=115 Participants Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg qd n=113 Participants Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tio 18 mcg qd n=113 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 participants	0 participants	1 participants	0 participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG Potassium increased	1 participants	0 participants	0 participants	0 participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG Atrial fibrillation	0 participants	0 participants	1 participants	0 participants

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Olo 5 mcg

Serious events: 3 serious events

Other events: 14 other events

Deaths: 0 deaths

Olo 10 mcg

Serious events: 8 serious events

Other events: 6 other events

Deaths: 0 deaths

Tiotropium (Tio) 18 mcg qd

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=109 participants at risk Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.	Olo 5 mcg n=115 participants at risk Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg n=113 participants at risk Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tiotropium (Tio) 18 mcg qd n=113 participants at risk Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Cardiac disorders Atrial fibrillation	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks
Cardiac disorders Cardiac ventricular disorder	0.00% 0/109 • 6 weeks	0.87% 1/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Eye disorders Retinal detachment	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.92% 1/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Infections and infestations Cellulitis staphylococcal	0.92% 1/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Infections and infestations Pneumonia	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks
Injury, poisoning and procedural complications Fracture displacement	0.92% 1/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.88% 1/113 • 6 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/109 • 6 weeks	0.87% 1/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.00% 0/109 • 6 weeks	0.87% 1/115 • 6 weeks	0.00% 0/113 • 6 weeks	0.00% 0/113 • 6 weeks
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.8% 2/109 • 6 weeks	0.00% 0/115 • 6 weeks	3.5% 4/113 • 6 weeks	0.88% 1/113 • 6 weeks
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/109 • 6 weeks	0.00% 0/115 • 6 weeks	0.88% 1/113 • 6 weeks	0.00% 0/113 • 6 weeks

Other adverse events

Measure	Placebo n=109 participants at risk Matching Placebo delivered by the Respimat resp. Aerolizer Inhaler.	Olo 5 mcg n=115 participants at risk Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	Olo 10 mcg n=113 participants at risk Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	Tiotropium (Tio) 18 mcg qd n=113 participants at risk Tiotropium (Tio) 18 mcg qd (morning) delivered by the HandiHaler
Infections and infestations Nasopharyngitis	3.7% 4/109 • 6 weeks	7.0% 8/115 • 6 weeks	3.5% 4/113 • 6 weeks	3.5% 4/113 • 6 weeks
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	3.7% 4/109 • 6 weeks	5.2% 6/115 • 6 weeks	2.7% 3/113 • 6 weeks	0.88% 1/113 • 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