Safety and Efficacy of BI 1744 CL in Patients With Chronic Obstructive Pulmonary Disease II

A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 ug] and 10 ug [2 Actuations of 5 ug]) Delivered by the Respimat® Inhaler, and 48 Weeks of Twice Daily Foradil® (12 µg) Delivered by the Aerolizer® Inhaler, in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00796653

Enrollment

937

Registered

2008-11-24

Start date

2009-01-31

Completion date

Unknown

Last updated

2014-06-27

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

Conditions

Pulmonary Disease, Chronic Obstructive

Brief summary

The primary objective of this study is to assess the long-term efficacy and safety of once daily treatment of BI 1744 CL inhalation solution (5 and 10 mcg) delivered via the Respimat® inhaler, in patients with COPD.

Interventions

DRUGOlodaterol (BI 1744)

Comparison of low and high doses on efficacy and safety in COPD patients

DRUGFormoterol

Active comparator with Olodaterol (BI 1744) on safety and efficacy in COPD patients

DRUGPlacebo

Placebo devices for comparison with Olodaterol (BI 1744) on safety and efficacy in COPD patients

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

1. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:post-bronchodilator FEV1\<80% of predicted normal (ECSC) and a post-bronchodilator FEV1/FVC \<70% at Visit 1 2. Male or female patients, 40 years of age or older 3. Patients must be current or ex-smokers with a smoking history of more than 10 pack years:

Exclusion criteria

1. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT \>x2 ULN, SGPT \>x2 ULN, bilirubin \>x2 ULN or creatinine \>x2 ULN 2. Patients with a history of asthma and/or total blood eosinophil count greater than 600/mm3 3. Patients with thyrotoxicosis, paroxysmal tachycardia (\>100 beats per minute) 4. Patients with a history of myocardial infarction within 1 year of screening visit, unstable or life-threatening cardiac arrhythmia, hospitalization for heart failure within the past year, known active tuberculosis, a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years, life-threatening pulmonary obstruction, cystic fibrosis, clinically evident bronchiectasis, significant alcohol or drug abuse 5. Patients who have undergone thoracotomy with pulmonary resection 6. Patients being treated with oral beta-adrenergics or oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. 7. Patients who regularly use daytime oxygen therapy for more than one hour per day. 8. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program 9. Pregnant or nursing women 10. Women of childbearing potential not using two effective methods of birth control (one barrier and one non-barrier).

Design outcomes

Primary

Measure	Time frame	Description
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Trough FEV1 Response at Week 24	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks	Baseline, Week 24	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis	Baseline, Week 24	This outcome measure describes the combined analysis of the trials NCT00793624 and NCT00796653. Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).

Secondary

Measure	Time frame	Description
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48	Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Trough FEV1 Response at Week 2	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 6	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 12	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 18	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 32	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 40	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FEV1 Response at Week 48	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.	Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FEV1 (0-3h) Response After 2 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FEV1 (0-3h) Response After 6 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FEV1 (0-3h) Response After 12 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FEV1 (0-3h) Response After 24 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FEV1 (0-3h) Response After 48 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks	Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2	Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6	Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12	Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24	Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48	Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Trough FVC Response at Week 2	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 6	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 12	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 18	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 24	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 32	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 40	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Trough FVC Response at Week 48	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.	Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FVC (0-3h) Response After 2 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks	Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FVC (0-3h) Response After 6 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks	Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FVC (0-3h) Response After 12 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks	Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FVC (0-3h) Response After 24 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks	Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak FVC (0-3h) Response After 48 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks	Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.
Peak Expiratory Flow Rate (PEFR) at Week 24	Week 24	Weekly mean pre-dose morning and evening PEFR. Results are from non-MMRM ANCOVA models by week, with Last observation carried forward (LOCF) up to each week. Fixed effects include treatment, tiotropium, strata and baseline.
Use of Rescue Medication at Week 24	Week 24	Mean number of puffs of rescue medication used per day (daytime/nighttime/total)
Patient's Global Rating (PGR) at 6 Weeks	Week 6	Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse).
Patient's Global Rating (PGR) at 12 Weeks	Week 12	Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse).
Patient's Global Rating (PGR) at 24 Weeks	Week 24	Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse).
Patient's Global Rating (PGR) at 48 Weeks	Week 48	Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse).
Mahler Transitional Dyspnea Index Focal Score at 6 Weeks	Baseline, Week 6	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 12 Weeks	Baseline, Week 12	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 18 Weeks	Baseline, Week 18	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 32 Weeks	Baseline, Week 32	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 40 Weeks	Baseline, Week 40	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Mahler Transitional Dyspnea Index Focal Score at 48 Weeks	Baseline, Week 48	Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	Baseline to end of study at 48 weeks.	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.
Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	Baseline to end of study at 48 weeks.	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.
Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	Baseline to end of study at 48 weeks.	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.
Number of COPD Exacerbations	Baseline to end of study at week 48 visit	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria.
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks	Baseline, Week 24	Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).
Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations	Baseline to end of study at 48 weeks.	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids.
Changes in Safety Parameters Related to Treatment	48 weeks	Occurence of cardiac disorders and investigations related to treatment.
Absolute Plasma Concentrations	within 2 hours before first study drug administration and 10 minutes post-dose at week 6, 12 and 18	Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means.
Number of COPD Exacerbations Requiring Hospitalization	Baseline to end of study at week 48 visit	Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization.
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks	Baseline, Week 48	Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks	Baseline, Week 12	Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis	Baseline, Week 24	Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). This is a combined analysis of the data from NCT00793624 and NCT00796653 showing adjusted values using a MMRM model.

Countries

Argentina, Brazil, Canada, Czechia, Denmark, Finland, Germany, Hong Kong, India, Italy, Malaysia, Norway, Philippines, Romania, Russia, South Africa, South Korea, Spain, Sweden, Thailand

Participant flow

Pre-assignment details

Three patients were randomized but not treated due to withdrawn consent and findings on pre-dose ECG prior to receiving study medication.

Participants by arm

Arm	Count
Placebo Matching Placebo delivered by the Respimat Inhaler.	235
Olo 5 mcg qd Olodaterol 5 mcg qd (morning) delivered by the Respimat Inhaler.	232
Olo 10 mcg qd Olodaterol 10 mcg qd (morning) delivered by the Respimat Inhaler.	234
Form 12 mcg Foradil 12 mcg bid (morning and evening) delivered by the Aerolizer Inhaler.	233
Total	934

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	19	16	16	16
Overall Study	Lack of Efficacy	8	1	3	2
Overall Study	Lost to Follow-up	2	1	2	3
Overall Study	Non compliance with protocol	2	2	0	2
Overall Study	Other reason not described above	4	9	7	4
Overall Study	Withdrawal by Subject	16	8	8	13

Baseline characteristics

Characteristic	Placebo	Olo 5 mcg qd	Olo 10 mcg qd	Form 12 mcg	Total
Age, Continuous	63.9 years STANDARD_DEVIATION 7.8	63.7 years STANDARD_DEVIATION 8.8	63.8 years STANDARD_DEVIATION 8.5	65.0 years STANDARD_DEVIATION 8.2	64.183 years STANDARD_DEVIATION 8.7
Sex: Female, Male Female	40 Participants	45 Participants	50 Participants	41 Participants	176 Participants
Sex: Female, Male Male	195 Participants	187 Participants	184 Participants	192 Participants	758 Participants
Tiotropium (Tio) Use Stratum Non-tiotropium	173 Number of participants	174 Number of participants	172 Number of participants	174 Number of participants	693 Number of participants
Tiotropium (Tio) Use Stratum Tiotropium	62 Number of participants	58 Number of participants	62 Number of participants	59 Number of participants	241 Number of participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	100 / 235	103 / 232	101 / 234	105 / 233
serious Total, serious adverse events	48 / 235	34 / 232	41 / 234	36 / 233

Outcome results

Primary

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks

Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24

Population: Full analysis set (FAS). FAS is defined as all randomized patients who received at least one dose of treatment and had both baseline data and at least one post-baseline measurement at or before 24 weeks for any of the co-primary efficacy variables.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	-0.013 Liter	Standard Error 0.014
Olo 5 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.116 Liter	Standard Error 0.014
Olo 10 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.140 Liter	Standard Error 0.014
Form 12 mcg	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.137 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.091, 0.167]Mixed Models Analysis

p-value: <0.000195% CI: [0.116, 0.191]Mixed Models Analysis

p-value: <0.000195% CI: [0.112, 0.188]Mixed Models Analysis

Primary

Mahler Transitional Dyspnea Index Focal Score at 24 Weeks

Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).

Time frame: Baseline, Week 24

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks	1.102 score on a scale	Standard Error 0.229
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks	1.504 score on a scale	Standard Error 0.225
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks	1.521 score on a scale	Standard Error 0.225
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks	1.703 score on a scale	Standard Error 0.228

p-value: 0.199995% CI: [-0.213, 1.018]Mixed Models Analysis

p-value: 0.181895% CI: [-0.196, 1.035]Mixed Models Analysis

p-value: 0.057295% CI: [-0.019, 1.222]Mixed Models Analysis

Primary

Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis

This outcome measure describes the combined analysis of the trials NCT00793624 and NCT00796653. Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement).

Time frame: Baseline, Week 24

Population: Full analysis sets (FAS) of the trials NCT00793624 and NCT00796653. FAS is defined as all randomized patients who received at least one dose of treatment and had both baseline data and at least one post-baseline measurement at or before 24 weeks for any of the co-primary efficacy variables.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis	1.471 score on a scale	Standard Error 0.155
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis	1.980 score on a scale	Standard Error 0.175
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis	1.996 score on a scale	Standard Error 0.17
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis	1.827 score on a scale	Standard Error 0.168

Comparison: Olo 5mcg minus placebop-value: 0.02795% CI: [0.058, 0.96]pattern mixture model

Comparison: Olo 10 mcg minus placebop-value: 0.020395% CI: [0.082, 0.967]pattern mixture model

Comparison: Form 12mcg minus placebop-value: 0.116695% CI: [-0.088, 0.799]pattern mixture model

Primary

Trough FEV1 Response at Week 24

Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 24	-0.055 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 24	-0.003 Liter	Standard Error 0.014
Olo 10 mcg qd	Trough FEV1 Response at Week 24	0.014 Liter	Standard Error 0.014
Form 12 mcg	Trough FEV1 Response at Week 24	-0.013 Liter	Standard Error 0.014

p-value: 0.005595% CI: [0.015, 0.09]Mixed Models Analysis

p-value: 0.000395% CI: [0.032, 0.106]Mixed Models Analysis

p-value: 0.02795% CI: [0.005, 0.08]Mixed Models Analysis

Secondary

Absolute Plasma Concentrations

Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means.

Time frame: within 2 hours before first study drug administration and 10 minutes post-dose at week 6, 12 and 18

Population: Pharmacokinetic set includes all patients in the treated set who had at least one valid olodaterol plasma concentration measurement after initial administration of study drug. This set is restricted to patients in either the Olodaterol 5 μg or 10 μg dose group.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Olo 5 mcg qd	Absolute Plasma Concentrations	3.920 pg/mL	Geometric Coefficient of Variation 50.51
Olo 10 mcg qd	Absolute Plasma Concentrations	6.977 pg/mL	Geometric Coefficient of Variation 68.643

Secondary

Changes in Safety Parameters Related to Treatment

Occurence of cardiac disorders and investigations related to treatment.

Time frame: 48 weeks

Population: Treated set.

Arm	Measure	Group	Value (NUMBER)
Placebo	Changes in Safety Parameters Related to Treatment	Alanine aminotransferase increased	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Ventricular extrasystoles	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Acute myocardial infarction	0.0 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Gamma-glutamyltransferase increased	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Myocardial infarction	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Angina unstable	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Atrial fibrillation	0.9 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Sinus tachycardia	0.0 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Electrocardiogram T wave inversion	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Blood creatine phosphokinase increased	0.0 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Aspartate aminotransferase increased	0.0 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Acute coronary syndrome	0.4 percentage of participants
Placebo	Changes in Safety Parameters Related to Treatment	Electrocardiogram ST segment depression	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Electrocardiogram T wave inversion	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Sinus tachycardia	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Electrocardiogram ST segment depression	0.4 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Atrial fibrillation	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Acute coronary syndrome	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Acute myocardial infarction	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Angina unstable	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Myocardial infarction	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Ventricular extrasystoles	0.4 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Alanine aminotransferase increased	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Aspartate aminotransferase increased	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Blood creatine phosphokinase increased	0.0 percentage of participants
Olo 5 mcg qd	Changes in Safety Parameters Related to Treatment	Gamma-glutamyltransferase increased	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Ventricular extrasystoles	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Gamma-glutamyltransferase increased	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Blood creatine phosphokinase increased	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Electrocardiogram ST segment depression	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Acute coronary syndrome	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Atrial fibrillation	0.9 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Sinus tachycardia	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Aspartate aminotransferase increased	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Angina unstable	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Alanine aminotransferase increased	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Acute myocardial infarction	0.4 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Electrocardiogram T wave inversion	0.0 percentage of participants
Olo 10 mcg qd	Changes in Safety Parameters Related to Treatment	Myocardial infarction	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Atrial fibrillation	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Acute coronary syndrome	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Electrocardiogram T wave inversion	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Ventricular extrasystoles	0.4 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Alanine aminotransferase increased	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Sinus tachycardia	0.9 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Gamma-glutamyltransferase increased	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Aspartate aminotransferase increased	0.4 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Myocardial infarction	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Electrocardiogram ST segment depression	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Acute myocardial infarction	0.0 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Blood creatine phosphokinase increased	0.4 percentage of participants
Form 12 mcg	Changes in Safety Parameters Related to Treatment	Angina unstable	0.0 percentage of participants

Secondary

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	-0.008 Liter	Standard Error 0.014
Olo 5 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.138 Liter	Standard Error 0.014
Olo 10 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.167 Liter	Standard Error 0.014
Form 12 mcg	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.163 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.108, 0.182]Mixed Models Analysis

p-value: <0.000195% CI: [0.138, 0.212]Mixed Models Analysis

p-value: <0.000195% CI: [0.133, 0.208]Mixed Models Analysis

Secondary

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.021 Liter	Standard Error 0.013
Olo 5 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.181 Liter	Standard Error 0.014
Olo 10 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.214 Liter	Standard Error 0.013
Form 12 mcg	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.183 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.123, 0.196]Mixed Models Analysis

p-value: <0.000195% CI: [0.157, 0.229]Mixed Models Analysis

p-value: <0.000195% CI: [0.126, 0.199]Mixed Models Analysis

Secondary

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	-0.025 Liter	Standard Error 0.014
Olo 5 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.093 Liter	Standard Error 0.014
Olo 10 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.116 Liter	Standard Error 0.014
Form 12 mcg	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.104 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.08, 0.156]Mixed Models Analysis

p-value: <0.000195% CI: [0.103, 0.18]Mixed Models Analysis

p-value: <0.000195% CI: [0.091, 0.168]Mixed Models Analysis

Secondary

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	-0.010 Liter	Standard Error 0.014
Olo 5 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.162 Liter	Standard Error 0.014
Olo 10 mcg qd	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.181 Liter	Standard Error 0.014
Form 12 mcg	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.174 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.136, 0.209]Mixed Models Analysis

p-value: <0.000195% CI: [0.155, 0.228]Mixed Models Analysis

p-value: <0.000195% CI: [0.148, 0.221]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks

Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.006 Liter	Standard Error 0.026
Olo 5 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.235 Liter	Standard Error 0.026
Olo 10 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.253 Liter	Standard Error 0.026
Form 12 mcg	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks	0.280 Liter	Standard Error 0.026

p-value: <0.000195% CI: [0.159, 0.299]Mixed Models Analysis

p-value: <0.000195% CI: [0.177, 0.317]Mixed Models Analysis

p-value: <0.000195% CI: [0.205, 0.345]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.012 Liter	Standard Error 0.026
Olo 5 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.212 Liter	Standard Error 0.026
Olo 10 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.225 Liter	Standard Error 0.026
Form 12 mcg	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks	0.253 Liter	Standard Error 0.026

p-value: <0.000195% CI: [0.128, 0.27]Mixed Models Analysis

p-value: <0.000195% CI: [0.142, 0.283]Mixed Models Analysis

p-value: <0.000195% CI: [0.17, 0.312]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.082 Liter	Standard Error 0.025
Olo 5 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.312 Liter	Standard Error 0.025
Olo 10 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.332 Liter	Standard Error 0.025
Form 12 mcg	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks	0.348 Liter	Standard Error 0.025

p-value: <0.000195% CI: [0.162, 0.299]Mixed Models Analysis

p-value: <0.000195% CI: [0.182, 0.318]Mixed Models Analysis

p-value: <0.000195% CI: [0.198, 0.334]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	-0.036 Liter	Standard Error 0.027
Olo 5 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.182 Liter	Standard Error 0.026
Olo 10 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.201 Liter	Standard Error 0.026
Form 12 mcg	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks	0.184 Liter	Standard Error 0.026

p-value: <0.000195% CI: [0.146, 0.29]Mixed Models Analysis

p-value: <0.000195% CI: [0.166, 0.309]Mixed Models Analysis

p-value: <0.000195% CI: [0.148, 0.292]Mixed Models Analysis

Secondary

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.027 Liter	Standard Error 0.025
Olo 5 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.277 Liter	Standard Error 0.026
Olo 10 mcg qd	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.276 Liter	Standard Error 0.025
Form 12 mcg	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks	0.307 Liter	Standard Error 0.026

p-value: <0.000195% CI: [0.182, 0.32]Mixed Models Analysis

p-value: <0.000195% CI: [0.18, 0.318]Mixed Models Analysis

p-value: <0.000195% CI: [0.212, 0.35]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 12 Weeks

Time frame: Baseline, Week 12

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 12 Weeks	1.080 score on a scale	Standard Error 0.224
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 12 Weeks	1.742 score on a scale	Standard Error 0.222
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 12 Weeks	1.747 score on a scale	Standard Error 0.224
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 12 Weeks	1.499 score on a scale	Standard Error 0.226

p-value: 0.031995% CI: [0.057, 1.267]Mixed Models Analysis

p-value: 0.031295% CI: [0.06, 1.274]Mixed Models Analysis

p-value: 0.177795% CI: [-0.191, 1.029]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 18 Weeks

Time frame: Baseline, Week 18

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 18 Weeks	1.0454 score on a scale	Standard Error 0.227
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 18 Weeks	1.470 score on a scale	Standard Error 0.223
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 18 Weeks	1.537 score on a scale	Standard Error 0.224
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 18 Weeks	1.579 score on a scale	Standard Error 0.227

p-value: 0.171495% CI: [-0.184, 1.035]Mixed Models Analysis

p-value: 0.114295% CI: [-0.119, 1.103]Mixed Models Analysis

p-value: 0.088895% CI: [-0.081, 1.15]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 32 Weeks

Time frame: Baseline, Week 32

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 32 Weeks	1.168 score on a scale	Standard Error 0.232
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 32 Weeks	1.658 score on a scale	Standard Error 0.228
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 32 Weeks	1.522 score on a scale	Standard Error 0.228
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 32 Weeks	1.477 score on a scale	Standard Error 0.229

p-value: 0.123595% CI: [-0.134, 1.113]Mixed Models Analysis

p-value: 0.266695% CI: [-0.271, 0.978]Mixed Models Analysis

p-value: 0.333595% CI: [-0.317, 0.934]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 40 Weeks

Time frame: Baseline, Week 40

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 40 Weeks	1.064 score on a scale	Standard Error 0.234
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 40 Weeks	1.377 score on a scale	Standard Error 0.229
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 40 Weeks	1.545 score on a scale	Standard Error 0.229
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 40 Weeks	1.178 score on a scale	Standard Error 0.231

p-value: 0.328795% CI: [-0.315, 0.941]Mixed Models Analysis

p-value: 0.134195% CI: [-0.148, 1.109]Mixed Models Analysis

p-value: 0.72295% CI: [-0.516, 0.745]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 48 Weeks

Time frame: Baseline, Week 48

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 48 Weeks	1.113 score on a scale	Standard Error 0.234
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 48 Weeks	1.510 score on a scale	Standard Error 0.231
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 48 Weeks	1.831 score on a scale	Standard Error 0.23
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 48 Weeks	1.280 score on a scale	Standard Error 0.232

p-value: 0.217695% CI: [-0.234, 1.027]Mixed Models Analysis

p-value: 0.025895% CI: [0.087, 1.348]Mixed Models Analysis

p-value: 0.604495% CI: [-0.466, 0.8]Mixed Models Analysis

Secondary

Mahler Transitional Dyspnea Index Focal Score at 6 Weeks

Time frame: Baseline, Week 6

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mahler Transitional Dyspnea Index Focal Score at 6 Weeks	0.980 score on a scale	Standard Error 0.221
Olo 5 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 6 Weeks	1.417 score on a scale	Standard Error 0.221
Olo 10 mcg qd	Mahler Transitional Dyspnea Index Focal Score at 6 Weeks	1.686 score on a scale	Standard Error 0.222
Form 12 mcg	Mahler Transitional Dyspnea Index Focal Score at 6 Weeks	1.444 score on a scale	Standard Error 0.224

p-value: 0.152495% CI: [-0.162, 1.036]Mixed Models Analysis

p-value: 0.021195% CI: [0.106, 1.307]Mixed Models Analysis

p-value: 0.131495% CI: [-0.139, 1.066]Mixed Models Analysis

Secondary

Number of COPD Exacerbations

Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria.

Time frame: Baseline to end of study at week 48 visit

Population: Treated set- all patients who received at least one dose of study medication

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Number of COPD Exacerbations	0.6890 Number of COPD ex. per patient year	Standard Error 0.0829
Olo 5 mcg qd	Number of COPD Exacerbations	0.5409 Number of COPD ex. per patient year	Standard Error 0.069
Olo 10 mcg qd	Number of COPD Exacerbations	0.5947 Number of COPD ex. per patient year	Standard Error 0.0736
Form 12 mcg	Number of COPD Exacerbations	0.7325 Number of COPD ex. per patient year	Standard Error 0.0861

p-value: 0.157195% CI: [0.5613, 1.0979]Negative binomial regression

p-value: 0.381495% CI: [0.6205, 1.2005]Negative binomial regression

p-value: 0.709895% CI: [0.7699, 1.468]Negative binomial regression

Secondary

Number of COPD Exacerbations Requiring Hospitalization

Time frame: Baseline to end of study at week 48 visit

Population: Treated set- all patients who received at least one dose of study medication

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Number of COPD Exacerbations Requiring Hospitalization	0.0986 Number of COPD ex. per patient year	Standard Error 0.0258
Olo 5 mcg qd	Number of COPD Exacerbations Requiring Hospitalization	0.0781 Number of COPD ex. per patient year	Standard Error 0.0221
Olo 10 mcg qd	Number of COPD Exacerbations Requiring Hospitalization	0.0993 Number of COPD ex. per patient year	Standard Error 0.0253
Form 12 mcg	Number of COPD Exacerbations Requiring Hospitalization	0.1025 Number of COPD ex. per patient year	Standard Error 0.0262

p-value: 0.532695% CI: [0.3814, 1.6464]Negative binomial regression

p-value: 0.982495% CI: [0.5038, 2.016]Negative binomial regression

p-value: 0.911295% CI: [0.5194, 2.0832]Negative binomial regression

Secondary

Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations

Time frame: Baseline to end of study at 48 weeks.

Population: Treated set- all patients who received at least one dose of study medication

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations	0.5548 Number of COPD ex. per patient year	Standard Error 0.0719
Olo 5 mcg qd	Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations	0.4128 Number of COPD ex. per patient year	Standard Error 0.0578
Olo 10 mcg qd	Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations	0.4351 Number of COPD ex. per patient year	Standard Error 0.0601
Form 12 mcg	Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations	0.5415 Number of COPD ex. per patient year	Standard Error 0.0699

p-value: 0.113695% CI: [0.5158, 1.0733]Negative binomial regression

p-value: 0.188795% CI: [0.5456, 1.1271]Negative binomial regression

p-value: 0.892595% CI: [0.6869, 1.387]Negative binomial regression

Secondary

Patient's Global Rating (PGR) at 12 Weeks

Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse).

Time frame: Week 12

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Patient's Global Rating (PGR) at 12 Weeks	3.3 score on a scale	Standard Error 0.1
Olo 5 mcg qd	Patient's Global Rating (PGR) at 12 Weeks	3.1 score on a scale	Standard Error 0.1
Olo 10 mcg qd	Patient's Global Rating (PGR) at 12 Weeks	3.0 score on a scale	Standard Error 0.1
Form 12 mcg	Patient's Global Rating (PGR) at 12 Weeks	3.0 score on a scale	Standard Error 0.1

p-value: 0.038895% CI: [-0.4, 0]Mixed Models Analysis

p-value: 0.003895% CI: [-0.5, -0.1]Mixed Models Analysis

p-value: 0.005395% CI: [-0.5, -0.1]Mixed Models Analysis

Secondary

Patient's Global Rating (PGR) at 24 Weeks

Time frame: Week 24

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Patient's Global Rating (PGR) at 24 Weeks	3.3 score on a scale	Standard Error 0.1
Olo 5 mcg qd	Patient's Global Rating (PGR) at 24 Weeks	3.1 score on a scale	Standard Error 0.1
Olo 10 mcg qd	Patient's Global Rating (PGR) at 24 Weeks	3.1 score on a scale	Standard Error 0.1
Form 12 mcg	Patient's Global Rating (PGR) at 24 Weeks	3.1 score on a scale	Standard Error 0.1

p-value: 0.055595% CI: [-0.4, 0]Mixed Models Analysis

p-value: 0.012295% CI: [-0.4, -0.1]Mixed Models Analysis

p-value: 0.014495% CI: [-0.4, -0.1]Mixed Models Analysis

Secondary

Patient's Global Rating (PGR) at 48 Weeks

Time frame: Week 48

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Patient's Global Rating (PGR) at 48 Weeks	3.2 score on a scale	Standard Error 0.1
Olo 5 mcg qd	Patient's Global Rating (PGR) at 48 Weeks	3.2 score on a scale	Standard Error 0.1
Olo 10 mcg qd	Patient's Global Rating (PGR) at 48 Weeks	3.0 score on a scale	Standard Error 0.1
Form 12 mcg	Patient's Global Rating (PGR) at 48 Weeks	3.2 score on a scale	Standard Error 0.1

p-value: 0.570795% CI: [-0.3, 0.1]Mixed Models Analysis

p-value: 0.081495% CI: [-0.4, 0]Mixed Models Analysis

p-value: 0.741395% CI: [-0.2, 0.2]Mixed Models Analysis

Secondary

Patient's Global Rating (PGR) at 6 Weeks

Time frame: Week 6

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Patient's Global Rating (PGR) at 6 Weeks	3.4 score on a scale	Standard Error 0.1
Olo 5 mcg qd	Patient's Global Rating (PGR) at 6 Weeks	3.1 score on a scale	Standard Error 0.1
Olo 10 mcg qd	Patient's Global Rating (PGR) at 6 Weeks	3.2 score on a scale	Standard Error 0.1
Form 12 mcg	Patient's Global Rating (PGR) at 6 Weeks	3.1 score on a scale	Standard Error 0.1

p-value: 0.016495% CI: [-0.4, 0]Mixed Models Analysis

p-value: 0.019695% CI: [-0.4, 0]Mixed Models Analysis

p-value: 0.004195% CI: [-0.5, -0.1]Mixed Models Analysis

Secondary

Peak Expiratory Flow Rate (PEFR) at Week 24

Weekly mean pre-dose morning and evening PEFR. Results are from non-MMRM ANCOVA models by week, with Last observation carried forward (LOCF) up to each week. Fixed effects include treatment, tiotropium, strata and baseline.

Time frame: Week 24

Population: FAS

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Peak Expiratory Flow Rate (PEFR) at Week 24	morning PEFR (N=225, 227, 226, 224)	196.789 L/min	Standard Error 3.27
Placebo	Peak Expiratory Flow Rate (PEFR) at Week 24	evening PEFR (N=224, 223, 227, 222)	202.505 L/min	Standard Error 3.281
Olo 5 mcg qd	Peak Expiratory Flow Rate (PEFR) at Week 24	evening PEFR (N=224, 223, 227, 222)	219.905 L/min	Standard Error 3.289
Olo 5 mcg qd	Peak Expiratory Flow Rate (PEFR) at Week 24	morning PEFR (N=225, 227, 226, 224)	210.496 L/min	Standard Error 3.253
Olo 10 mcg qd	Peak Expiratory Flow Rate (PEFR) at Week 24	morning PEFR (N=225, 227, 226, 224)	217.660 L/min	Standard Error 3.274
Olo 10 mcg qd	Peak Expiratory Flow Rate (PEFR) at Week 24	evening PEFR (N=224, 223, 227, 222)	225.380 L/min	Standard Error 3.281
Form 12 mcg	Peak Expiratory Flow Rate (PEFR) at Week 24	morning PEFR (N=225, 227, 226, 224)	211.038 L/min	Standard Error 3.299
Form 12 mcg	Peak Expiratory Flow Rate (PEFR) at Week 24	evening PEFR (N=224, 223, 227, 222)	218.321 L/min	Standard Error 3.321

Comparison: Comparison for weekly mean daytime rescue usep-value: 0.002195% CI: [5.004, 22.411]ANCOVA

Comparison: Comparison for weekly mean daytime rescue usep-value: <0.000195% CI: [12.158, 29.584]ANCOVA

Comparison: Comparison for weekly mean daytime rescue usep-value: 0.001495% CI: [5.506, 22.991]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: 0.000195% CI: [8.64, 26.16]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: <0.000195% CI: [14.153, 31.596]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: 0.000495% CI: [7.032, 24.599]ANCOVA

Secondary

Peak FEV1 (0-3h) Response After 12 Weeks

Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FEV1 (0-3h) Response After 12 Weeks	0.064 Liter	Standard Error 0.014
Olo 5 mcg qd	Peak FEV1 (0-3h) Response After 12 Weeks	0.206 Liter	Standard Error 0.014
Olo 10 mcg qd	Peak FEV1 (0-3h) Response After 12 Weeks	0.232 Liter	Standard Error 0.014
Form 12 mcg	Peak FEV1 (0-3h) Response After 12 Weeks	0.228 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.103, 0.18]Mixed Models Analysis

p-value: <0.000195% CI: [0.129, 0.207]Mixed Models Analysis

p-value: <0.000195% CI: [0.125, 0.203]Mixed Models Analysis

Secondary

Peak FEV1 (0-3h) Response After 24 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FEV1 (0-3h) Response After 24 Weeks	0.060 Liter	Standard Error 0.015
Olo 5 mcg qd	Peak FEV1 (0-3h) Response After 24 Weeks	0.183 Liter	Standard Error 0.014
Olo 10 mcg qd	Peak FEV1 (0-3h) Response After 24 Weeks	0.211 Liter	Standard Error 0.014
Form 12 mcg	Peak FEV1 (0-3h) Response After 24 Weeks	0.203 Liter	Standard Error 0.015

p-value: <0.000195% CI: [0.084, 0.163]Mixed Models Analysis

p-value: <0.000195% CI: [0.112, 0.191]Mixed Models Analysis

p-value: <0.000195% CI: [0.104, 0.183]Mixed Models Analysis

Secondary

Peak FEV1 (0-3h) Response After 2 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FEV1 (0-3h) Response After 2 Weeks	0.099 Liter	Standard Error 0.014
Olo 5 mcg qd	Peak FEV1 (0-3h) Response After 2 Weeks	0.260 Liter	Standard Error 0.014
Olo 10 mcg qd	Peak FEV1 (0-3h) Response After 2 Weeks	0.278 Liter	Standard Error 0.014
Form 12 mcg	Peak FEV1 (0-3h) Response After 2 Weeks	0.253 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.122, 0.199]Mixed Models Analysis

p-value: <0.000195% CI: [0.14, 0.216]Mixed Models Analysis

p-value: <0.000195% CI: [0.115, 0.191]Mixed Models Analysis

Secondary

Peak FEV1 (0-3h) Response After 48 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FEV1 (0-3h) Response After 48 Weeks	0.052 Liter	Standard Error 0.015
Olo 5 mcg qd	Peak FEV1 (0-3h) Response After 48 Weeks	0.163 Liter	Standard Error 0.015
Olo 10 mcg qd	Peak FEV1 (0-3h) Response After 48 Weeks	0.178 Liter	Standard Error 0.015
Form 12 mcg	Peak FEV1 (0-3h) Response After 48 Weeks	0.170 Liter	Standard Error 0.015

p-value: <0.000195% CI: [0.071, 0.152]Mixed Models Analysis

p-value: <0.000195% CI: [0.086, 0.166]Mixed Models Analysis

p-value: <0.000195% CI: [0.078, 0.158]Mixed Models Analysis

Secondary

Peak FEV1 (0-3h) Response After 6 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FEV1 (0-3h) Response After 6 Weeks	0.066 Liter	Standard Error 0.014
Olo 5 mcg qd	Peak FEV1 (0-3h) Response After 6 Weeks	0.235 Liter	Standard Error 0.014
Olo 10 mcg qd	Peak FEV1 (0-3h) Response After 6 Weeks	0.248 Liter	Standard Error 0.014
Form 12 mcg	Peak FEV1 (0-3h) Response After 6 Weeks	0.242 Liter	Standard Error 0.014

p-value: <0.000195% CI: [0.13, 0.207]Mixed Models Analysis

p-value: <0.000195% CI: [0.143, 0.22]Mixed Models Analysis

p-value: <0.000195% CI: [0.137, 0.214]Mixed Models Analysis

Secondary

Peak FVC (0-3h) Response After 12 Weeks

Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FVC (0-3h) Response After 12 Weeks	0.171 Liter	Standard Error 0.028
Olo 5 mcg qd	Peak FVC (0-3h) Response After 12 Weeks	0.386 Liter	Standard Error 0.027
Olo 10 mcg qd	Peak FVC (0-3h) Response After 12 Weeks	0.396 Liter	Standard Error 0.027
Form 12 mcg	Peak FVC (0-3h) Response After 12 Weeks	0.436 Liter	Standard Error 0.028

p-value: <0.000195% CI: [0.141, 0.289]Mixed Models Analysis

p-value: <0.000195% CI: [0.151, 0.3]Mixed Models Analysis

p-value: <0.000195% CI: [0.191, 0.34]Mixed Models Analysis

Secondary

Peak FVC (0-3h) Response After 24 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FVC (0-3h) Response After 24 Weeks	0.189 Liter	Standard Error 0.028
Olo 5 mcg qd	Peak FVC (0-3h) Response After 24 Weeks	0.371 Liter	Standard Error 0.028
Olo 10 mcg qd	Peak FVC (0-3h) Response After 24 Weeks	0.369 Liter	Standard Error 0.028
Form 12 mcg	Peak FVC (0-3h) Response After 24 Weeks	0.397 Liter	Standard Error 0.028

p-value: <0.000195% CI: [0.106, 0.258]Mixed Models Analysis

p-value: <0.000195% CI: [0.105, 0.256]Mixed Models Analysis

p-value: <0.000195% CI: [0.132, 0.283]Mixed Models Analysis

Secondary

Peak FVC (0-3h) Response After 2 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FVC (0-3h) Response After 2 Weeks	0.247 Liter	Standard Error 0.027
Olo 5 mcg qd	Peak FVC (0-3h) Response After 2 Weeks	0.480 Liter	Standard Error 0.027
Olo 10 mcg qd	Peak FVC (0-3h) Response After 2 Weeks	0.476 Liter	Standard Error 0.027
Form 12 mcg	Peak FVC (0-3h) Response After 2 Weeks	0.495 Liter	Standard Error 0.027

p-value: <0.000195% CI: [0.16, 0.306]Mixed Models Analysis

p-value: <0.000195% CI: [0.156, 0.302]Mixed Models Analysis

p-value: <0.000195% CI: [0.175, 0.321]Mixed Models Analysis

Secondary

Peak FVC (0-3h) Response After 48 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FVC (0-3h) Response After 48 Weeks	0.137 Liter	Standard Error 0.029
Olo 5 mcg qd	Peak FVC (0-3h) Response After 48 Weeks	0.325 Liter	Standard Error 0.028
Olo 10 mcg qd	Peak FVC (0-3h) Response After 48 Weeks	0.352 Liter	Standard Error 0.028
Form 12 mcg	Peak FVC (0-3h) Response After 48 Weeks	0.329 Liter	Standard Error 0.028

p-value: <0.000195% CI: [0.111, 0.265]Mixed Models Analysis

p-value: <0.000195% CI: [0.138, 0.291]Mixed Models Analysis

p-value: <0.000195% CI: [0.115, 0.269]Mixed Models Analysis

Secondary

Peak FVC (0-3h) Response After 6 Weeks

Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Peak FVC (0-3h) Response After 6 Weeks	0.196 Liter	Standard Error 0.027
Olo 5 mcg qd	Peak FVC (0-3h) Response After 6 Weeks	0.443 Liter	Standard Error 0.027
Olo 10 mcg qd	Peak FVC (0-3h) Response After 6 Weeks	0.417 Liter	Standard Error 0.027
Form 12 mcg	Peak FVC (0-3h) Response After 6 Weeks	0.450 Liter	Standard Error 0.027

p-value: <0.000195% CI: [0.174, 0.321]Mixed Models Analysis

p-value: <0.000195% CI: [0.148, 0.295]Mixed Models Analysis

p-value: <0.000195% CI: [0.18, 0.328]Mixed Models Analysis

Secondary

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks

Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).

Time frame: Baseline, Week 12

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks	42.679 score on a scale	Standard Error 0.983
Olo 5 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks	40.054 score on a scale	Standard Error 0.955
Olo 10 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks	40.190 score on a scale	Standard Error 0.963
Form 12 mcg	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks	39.521 score on a scale	Standard Error 0.975

p-value: 0.049195% CI: [-5.241, -0.01]Mixed Models Analysis

p-value: 0.063695% CI: [-5.119, 0.141]Mixed Models Analysis

p-value: 0.019495% CI: [-5.806, -0.511]Mixed Models Analysis

Secondary

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks

Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).

Time frame: Baseline, Week 24

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks	42.120 score on a scale	Standard Error 0.995
Olo 5 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks	38.970 score on a scale	Standard Error 0.965
Olo 10 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks	38.597 score on a scale	Standard Error 0.969
Form 12 mcg	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks	40.704 score on a scale	Standard Error 0.984

p-value: 0.019795% CI: [-5.796, -0.503]Mixed Models Analysis

p-value: 0.009495% CI: [-6.18, -0.867]Mixed Models Analysis

p-value: 0.299595% CI: [-4.093, 1.261]Mixed Models Analysis

Secondary

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis

Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). This is a combined analysis of the data from NCT00793624 and NCT00796653 showing adjusted values using a MMRM model.

Time frame: Baseline, Week 24

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis	41.639 score on a scale	Standard Error 0.718
Olo 5 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis	38.794 score on a scale	Standard Error 0.693
Olo 10 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis	38.205 score on a scale	Standard Error 0.695
Form 12 mcg	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis	40.391 score on a scale	Standard Error 0.699

Comparison: Olo 5 mcg minus placebop-value: 0.003495% CI: [-4.751, -0.94]Mixed Models Analysis

Comparison: Olo 10 mcg minus placebop-value: 0.000495% CI: [-5.343, -1.525]Mixed Models Analysis

Comparison: Form 12 mcg minus placebop-value: 0.200995% CI: [-3.161, 0.665]Mixed Models Analysis

Secondary

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks

Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations).

Time frame: Baseline, Week 48

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks	39.914 score on a scale	Standard Error 1.022
Olo 5 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks	39.562 score on a scale	Standard Error 0.986
Olo 10 mcg qd	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks	38.824 score on a scale	Standard Error 0.991
Form 12 mcg	Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks	40.025 score on a scale	Standard Error 0.996

p-value: 0.799595% CI: [-3.068, 2.365]Mixed Models Analysis

p-value: 0.433695% CI: [-3.818, 1.639]Mixed Models Analysis

p-value: 0.936595% CI: [-2.625, 2.848]Mixed Models Analysis

Secondary

Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation

Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.

Time frame: Baseline to end of study at 48 weeks.

Arm	Measure	Value (MEAN)
Placebo	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	173 Days
Olo 5 mcg qd	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	177 Days
Olo 10 mcg qd	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	252 Days
Form 12 mcg	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	270 Days
Olo 10 mcg qd (Tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	252 Days
Olo 10 mcg qd(Non-tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	234 Days
Form 12 mcg (Tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	149 Days
Form 12 mcg (Non-tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation	232 Days

p-value: 0.194695% CI: [0.58, 1.111]Log Rank

p-value: 0.407195% CI: [0.634, 1.198]Log Rank

p-value: 0.640495% CI: [0.67, 1.267]Log Rank

Secondary

Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization

Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.

Time frame: Baseline to end of study at 48 weeks.

Arm	Measure	Value (MEAN)
Placebo	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Olo 5 mcg qd	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Olo 10 mcg qd	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Form 12 mcg	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Olo 10 mcg qd (Tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Olo 10 mcg qd(Non-tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Form 12 mcg (Tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	NA Days
Form 12 mcg (Non-tiotropium)	Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization	368.0 Days

p-value: 0.294295% CI: [0.336, 1.399]Log Rank

p-value: 0.859495% CI: [0.493, 1.82]Log Rank

p-value: 0.546695% CI: [0.405, 1.593]Log Rank

Secondary

Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation

Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.

Time frame: Baseline to end of study at 48 weeks.

Arm	Measure	Value (MEAN)
Placebo	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	176 Days
Olo 5 mcg qd	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	214 Days
Olo 10 mcg qd	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	264 Days
Form 12 mcg	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	312 Days
Olo 10 mcg qd (Tiotropium)	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	324 Days
Olo 10 mcg qd(Non-tiotropium)	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	327 Days
Form 12 mcg (Tiotropium)	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	190 Days
Form 12 mcg (Non-tiotropium)	Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation	325 Days

p-value: 0.249495% CI: [0.566, 1.15]Log Rank

p-value: 0.200695% CI: [0.555, 1.126]Log Rank

p-value: 0.579595% CI: [0.637, 1.279]Log Rank

Secondary

Trough FEV1 Response at Week 12

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 12	-0.041 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 12	0.018 Liter	Standard Error 0.013
Olo 10 mcg qd	Trough FEV1 Response at Week 12	0.052 Liter	Standard Error 0.013
Form 12 mcg	Trough FEV1 Response at Week 12	0.024 Liter	Standard Error 0.014

p-value: 0.001795% CI: [0.022, 0.095]Mixed Models Analysis

p-value: <0.000195% CI: [0.057, 0.13]Mixed Models Analysis

p-value: 0.000595% CI: [0.028, 0.101]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 18

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 18	-0.036 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 18	0.013 Liter	Standard Error 0.014
Olo 10 mcg qd	Trough FEV1 Response at Week 18	0.049 Liter	Standard Error 0.013
Form 12 mcg	Trough FEV1 Response at Week 18	0.015 Liter	Standard Error 0.014

p-value: 0.008595% CI: [0.013, 0.087]Mixed Models Analysis

p-value: <0.000195% CI: [0.049, 0.122]Mixed Models Analysis

p-value: 0.006795% CI: [0.014, 0.088]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 2

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 2	-0.016 Liter	Standard Error 0.013
Olo 5 mcg qd	Trough FEV1 Response at Week 2	0.053 Liter	Standard Error 0.013
Olo 10 mcg qd	Trough FEV1 Response at Week 2	0.103 Liter	Standard Error 0.013
Form 12 mcg	Trough FEV1 Response at Week 2	0.033 Liter	Standard Error 0.013

p-value: 0.000295% CI: [0.033, 0.105]Mixed Models Analysis

p-value: <0.000195% CI: [0.083, 0.155]Mixed Models Analysis

p-value: 0.007195% CI: [0.013, 0.085]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 32

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 32	-0.039 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 32	0.023 Liter	Standard Error 0.014
Olo 10 mcg qd	Trough FEV1 Response at Week 32	0.034 Liter	Standard Error 0.014
Form 12 mcg	Trough FEV1 Response at Week 32	0.009 Liter	Standard Error 0.014

p-value: 0.001295% CI: [0.025, 0.1]Mixed Models Analysis

p-value: 0.000295% CI: [0.035, 0.11]Mixed Models Analysis

p-value: 0.011795% CI: [0.011, 0.086]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 40

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 40	-0.043 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 40	0.019 Liter	Standard Error 0.014
Olo 10 mcg qd	Trough FEV1 Response at Week 40	0.041 Liter	Standard Error 0.014
Form 12 mcg	Trough FEV1 Response at Week 40	0.013 Liter	Standard Error 0.014

p-value: 0.001495% CI: [0.024, 0.099]Mixed Models Analysis

p-value: <0.000195% CI: [0.047, 0.122]Mixed Models Analysis

p-value: 0.003595% CI: [0.019, 0.094]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 48

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 48	-0.060 Liter	Standard Error 0.014
Olo 5 mcg qd	Trough FEV1 Response at Week 48	-0.016 Liter	Standard Error 0.014
Olo 10 mcg qd	Trough FEV1 Response at Week 48	-0.001 Liter	Standard Error 0.014
Form 12 mcg	Trough FEV1 Response at Week 48	-0.024 Liter	Standard Error 0.014

p-value: 0.022895% CI: [0.006, 0.082]Mixed Models Analysis

p-value: 0.002495% CI: [0.021, 0.097]Mixed Models Analysis

p-value: 0.066495% CI: [-0.002, 0.074]Mixed Models Analysis

Secondary

Trough FEV1 Response at Week 6

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FEV1 Response at Week 6	-0.036 Liter	Standard Error 0.013
Olo 5 mcg qd	Trough FEV1 Response at Week 6	0.047 Liter	Standard Error 0.013
Olo 10 mcg qd	Trough FEV1 Response at Week 6	0.068 Liter	Standard Error 0.013
Form 12 mcg	Trough FEV1 Response at Week 6	0.034 Liter	Standard Error 0.013

p-value: <0.000195% CI: [0.048, 0.12]Mixed Models Analysis

p-value: <0.000195% CI: [0.068, 0.141]Mixed Models Analysis

p-value: 0.000195% CI: [0.034, 0.106]Mixed Models Analysis

Secondary

Trough FVC Response at Week 12

Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect.

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 12	-0.041 Liter	Standard Error 0.026
Olo 5 mcg qd	Trough FVC Response at Week 12	0.062 Liter	Standard Error 0.026
Olo 10 mcg qd	Trough FVC Response at Week 12	0.062 Liter	Standard Error 0.026
Form 12 mcg	Trough FVC Response at Week 12	0.070 Liter	Standard Error 0.026

p-value: 0.004595% CI: [0.032, 0.173]Mixed Models Analysis

p-value: 0.004695% CI: [0.032, 0.173]Mixed Models Analysis

p-value: 0.002395% CI: [0.039, 0.181]Mixed Models Analysis

Secondary

Trough FVC Response at Week 18

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 18	-0.014 Liter	Standard Error 0.027
Olo 5 mcg qd	Trough FVC Response at Week 18	0.084 Liter	Standard Error 0.026
Olo 10 mcg qd	Trough FVC Response at Week 18	0.107 Liter	Standard Error 0.026
Form 12 mcg	Trough FVC Response at Week 18	0.064 Liter	Standard Error 0.026

p-value: 0.007795% CI: [0.026, 0.169]Mixed Models Analysis

p-value: 0.000995% CI: [0.05, 0.193]Mixed Models Analysis

p-value: 0.033995% CI: [0.006, 0.149]Mixed Models Analysis

Secondary

Trough FVC Response at Week 2

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 2	0.030 Liter	Standard Error 0.026
Olo 5 mcg qd	Trough FVC Response at Week 2	0.118 Liter	Standard Error 0.026
Olo 10 mcg qd	Trough FVC Response at Week 2	0.173 Liter	Standard Error 0.026
Form 12 mcg	Trough FVC Response at Week 2	0.111 Liter	Standard Error 0.026

p-value: 0.013395% CI: [0.018, 0.157]Mixed Models Analysis

p-value: <0.000195% CI: [0.073, 0.212]Mixed Models Analysis

p-value: 0.021295% CI: [0.012, 0.151]Mixed Models Analysis

Secondary

Trough FVC Response at Week 24

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 24	-0.044 Liter	Standard Error 0.027
Olo 5 mcg qd	Trough FVC Response at Week 24	0.023 Liter	Standard Error 0.026
Olo 10 mcg qd	Trough FVC Response at Week 24	0.019 Liter	Standard Error 0.026
Form 12 mcg	Trough FVC Response at Week 24	-0.005 Liter	Standard Error 0.027

p-value: 0.071895% CI: [-0.006, 0.139]Mixed Models Analysis

p-value: 0.086395% CI: [-0.009, 0.135]Mixed Models Analysis

p-value: 0.298295% CI: [-0.034, 0.111]Mixed Models Analysis

Secondary

Trough FVC Response at Week 32

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 32	-0.007 Liter	Standard Error 0.027
Olo 5 mcg qd	Trough FVC Response at Week 32	0.081 Liter	Standard Error 0.027
Olo 10 mcg qd	Trough FVC Response at Week 32	0.063 Liter	Standard Error 0.027
Form 12 mcg	Trough FVC Response at Week 32	0.036 Liter	Standard Error 0.027

p-value: 0.01995% CI: [0.014, 0.16]Mixed Models Analysis

p-value: 0.060195% CI: [-0.003, 0.143]Mixed Models Analysis

p-value: 0.257395% CI: [-0.031, 0.115]Mixed Models Analysis

Secondary

Trough FVC Response at Week 40

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 40	-0.016 Liter	Standard Error 0.027
Olo 5 mcg qd	Trough FVC Response at Week 40	0.071 Liter	Standard Error 0.027
Olo 10 mcg qd	Trough FVC Response at Week 40	0.105 Liter	Standard Error 0.027
Form 12 mcg	Trough FVC Response at Week 40	0.037 Liter	Standard Error 0.027

p-value: 0.0295% CI: [0.014, 0.16]Mixed Models Analysis

p-value: 0.001395% CI: [0.047, 0.194]Mixed Models Analysis

p-value: 0.159895% CI: [-0.021, 0.126]Mixed Models Analysis

Secondary

Trough FVC Response at Week 48

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 48	-0.069 Liter	Standard Error 0.027
Olo 5 mcg qd	Trough FVC Response at Week 48	0.012 Liter	Standard Error 0.027
Olo 10 mcg qd	Trough FVC Response at Week 48	0.032 Liter	Standard Error 0.027
Form 12 mcg	Trough FVC Response at Week 48	-0.031 Liter	Standard Error 0.027

p-value: 0.030795% CI: [0.008, 0.155]Mixed Models Analysis

p-value: 0.007395% CI: [0.027, 0.175]Mixed Models Analysis

p-value: 0.314795% CI: [-0.036, 0.112]Mixed Models Analysis

Secondary

Trough FVC Response at Week 6

Time frame: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Trough FVC Response at Week 6	-0.014 Liter	Standard Error 0.026
Olo 5 mcg qd	Trough FVC Response at Week 6	0.113 Liter	Standard Error 0.026
Olo 10 mcg qd	Trough FVC Response at Week 6	0.101 Liter	Standard Error 0.026
Form 12 mcg	Trough FVC Response at Week 6	0.085 Liter	Standard Error 0.026

p-value: 0.000495% CI: [0.057, 0.197]Mixed Models Analysis

p-value: 0.001295% CI: [0.045, 0.185]Mixed Models Analysis

p-value: 0.005695% CI: [0.029, 0.169]Mixed Models Analysis

Secondary

Use of Rescue Medication at Week 24

Mean number of puffs of rescue medication used per day (daytime/nighttime/total)

Time frame: Week 24

Population: FAS

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Use of Rescue Medication at Week 24	Daytime	1.189 Number of puffs	Standard Error 0.089
Placebo	Use of Rescue Medication at Week 24	Total	2.893 Number of puffs	Standard Error 0.187
Placebo	Use of Rescue Medication at Week 24	Nighttime	1.713 Number of puffs	Standard Error 0.112
Olo 5 mcg qd	Use of Rescue Medication at Week 24	Daytime	1.036 Number of puffs	Standard Error 0.089
Olo 5 mcg qd	Use of Rescue Medication at Week 24	Total	2.470 Number of puffs	Standard Error 0.187
Olo 5 mcg qd	Use of Rescue Medication at Week 24	Nighttime	1.435 Number of puffs	Standard Error 0.111
Olo 10 mcg qd	Use of Rescue Medication at Week 24	Nighttime	1.348 Number of puffs	Standard Error 0.112
Olo 10 mcg qd	Use of Rescue Medication at Week 24	Daytime	0.923 Number of puffs	Standard Error 0.089
Olo 10 mcg qd	Use of Rescue Medication at Week 24	Total	2.277 Number of puffs	Standard Error 0.188
Form 12 mcg	Use of Rescue Medication at Week 24	Daytime	0.967 Number of puffs	Standard Error 0.09
Form 12 mcg	Use of Rescue Medication at Week 24	Total	2.353 Number of puffs	Standard Error 0.19
Form 12 mcg	Use of Rescue Medication at Week 24	Nighttime	1.393 Number of puffs	Standard Error 0.113

Comparison: Comparison for weekly mean daytime rescue usep-value: 0.205795% CI: [-0.391, -0.084]ANCOVA

Comparison: Comparison for weekly mean daytime rescue usep-value: 0.028495% CI: [-0.504, -0.028]ANCOVA

Comparison: Comparison for weekly mean daytime rescue usep-value: 0.068595% CI: [-0.461, 0.017]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: 0.067495% CI: [-0.576, 0.02]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: 0.016395% CI: [-0.662, -0.067]ANCOVA

Comparison: Comparison for weekly mean nighttime rescue usep-value: 0.036495% CI: [-0.62, -0.02]ANCOVA

Comparison: Comparison for weekly mean daily (24h) rescue usep-value: 0.095995% CI: [-0.922, 0.075]ANCOVA

Comparison: Comparison for weekly mean daily (24h) rescue usep-value: 0.015595% CI: [-1.115, -0.117]ANCOVA

Comparison: Comparison for weekly mean daily (24h) rescue usep-value: 0.034795% CI: [-1.042, -0.039]ANCOVA

Source: ClinicalTrials.gov · Data processed: Mar 10, 2026

Safety and Efficacy of BI 1744 CL in Patients With Chronic Obstructive Pulmonary Disease II

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks

Mahler Transitional Dyspnea Index Focal Score at 24 Weeks

Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis

Trough FEV1 Response at Week 24

Absolute Plasma Concentrations

Changes in Safety Parameters Related to Treatment

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks

Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks

Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks

Mahler Transitional Dyspnea Index Focal Score at 12 Weeks

Mahler Transitional Dyspnea Index Focal Score at 18 Weeks

Mahler Transitional Dyspnea Index Focal Score at 32 Weeks

Mahler Transitional Dyspnea Index Focal Score at 40 Weeks

Mahler Transitional Dyspnea Index Focal Score at 48 Weeks

Mahler Transitional Dyspnea Index Focal Score at 6 Weeks

Number of COPD Exacerbations

Number of COPD Exacerbations Requiring Hospitalization

Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations

Patient's Global Rating (PGR) at 12 Weeks

Patient's Global Rating (PGR) at 24 Weeks

Patient's Global Rating (PGR) at 48 Weeks

Patient's Global Rating (PGR) at 6 Weeks

Peak Expiratory Flow Rate (PEFR) at Week 24

Peak FEV1 (0-3h) Response After 12 Weeks

Peak FEV1 (0-3h) Response After 24 Weeks

Peak FEV1 (0-3h) Response After 2 Weeks

Peak FEV1 (0-3h) Response After 48 Weeks

Peak FEV1 (0-3h) Response After 6 Weeks

Peak FVC (0-3h) Response After 12 Weeks

Peak FVC (0-3h) Response After 24 Weeks

Peak FVC (0-3h) Response After 2 Weeks

Peak FVC (0-3h) Response After 48 Weeks

Peak FVC (0-3h) Response After 6 Weeks

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis

Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks

Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation

Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization

Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation

Trough FEV1 Response at Week 12

Trough FEV1 Response at Week 18

Trough FEV1 Response at Week 2

Trough FEV1 Response at Week 32

Trough FEV1 Response at Week 40

Trough FEV1 Response at Week 48

Trough FEV1 Response at Week 6

Trough FVC Response at Week 12

Trough FVC Response at Week 18

Trough FVC Response at Week 2

Trough FVC Response at Week 24

Trough FVC Response at Week 32

Trough FVC Response at Week 40