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

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00796653
• Other study ID #: 1222.14
• Secondary ID: 2008-001934-28
• Status: Completed
• Phase: Phase 3
• First received: November 21, 2008
• Last updated: June 17, 2014
• Start date: January 2009

Study information

• Verified date: June 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica)Brazil: National Health Surveillance AgencyCanada: Health Canada - Therapeutic Products DirectorateCzech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10Denmark: The Danish Medicines AgencyFinland: Finnish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesHong Kong: Department of HealthIndia: Drugs Controller General of IndiaItaly: Comitato Etico Centrale dell'IRCCS Fondazione Salvatore Maugeri di PaviaKorea, Republic of: Korea Food and Drug AdministrationMalaysia: Ministry of HealthNorway: Norwegian Medicines Agency (Statens Legemiddelverk)Philippines: Department of HealthRomania: National Medicines Agency, BucharestRussia: Ministry of Healthcare and Social Development of Russian Federation, MoscowSouth Africa: Medicines Control CouncilSpain: Agencia Espanola del Medicamento y Productos SanitariosSweden: Medical Products Agency Regional Ethics Committee of UmeåThailand: Ministry of Public Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 937
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Olodaterol (BI 1744)
Comparison of low and high doses on efficacy and safety in COPD patients
• Olodaterol (BI 1744)
Comparison of low and high doses on efficacy and safety in COPD patients
• Formoterol
Active comparator with Olodaterol (BI 1744) on safety and efficacy in COPD patients
• Placebo
Placebo devices for comparison with Olodaterol (BI 1744) on safety and efficacy in COPD patients

Locations

Country	Name	City	State
Argentina	1222.14.5004 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1222.14.5005 Boehringer Ingelheim Investigational Site	Florencio Varela
Argentina	1222.14.5003 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	1222.14.5001 Boehringer Ingelheim Investigational Site	Mendoza
Argentina	1222.14.5002 Boehringer Ingelheim Investigational Site	Quilmes
Brazil	1222.14.5106 Boehringer Ingelheim Investigational Site	Florianopolis
Brazil	1222.14.5101 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1222.14.5103 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1222.14.5104 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1222.14.5102 Boehringer Ingelheim Investigational Site	Recife
Brazil	1222.14.5105 Boehringer Ingelheim Investigational Site	Sao Paulo
Canada	1222.14.4005 Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	1222.14.4008 Boehringer Ingelheim Investigational Site	Grimsby	Ontario
Canada	1222.14.4002 Boehringer Ingelheim Investigational Site	Kelowna	British Columbia
Canada	1222.14.4014 Boehringer Ingelheim Investigational Site	Mississauga	Ontario
Canada	1222.14.4009 Boehringer Ingelheim Investigational Site	Moncton	New Brunswick
Canada	1222.14.4012 Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	1222.14.4007 Boehringer Ingelheim Investigational Site	Newmarket	Ontario
Canada	1222.14.4013 Boehringer Ingelheim Investigational Site	Ottawa	Ontario
Canada	1222.14.4006 Boehringer Ingelheim Investigational Site	Quebec
Canada	1222.14.4011 Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan
Canada	1222.14.4001 Boehringer Ingelheim Investigational Site	Scarborough	Ontario
Canada	1222.14.4015 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec
Canada	1222.14.4010 Boehringer Ingelheim Investigational Site	St. John's	Newfoundland and Labrador
Canada	1222.14.4004 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia
Czech Republic	1222.14.6004 Boehringer Ingelheim Investigational Site	Brno
Czech Republic	1222.14.6003 Boehringer Ingelheim Investigational Site	Hradec Kralove
Czech Republic	1222.14.6002 Boehringer Ingelheim Investigational Site	Kyjov
Czech Republic	1222.14.6001 Boehringer Ingelheim Investigational Site	Znojmo
Denmark	1222.14.4602 Boehringer Ingelheim Investigational Site	Helsingør
Denmark	1222.14.4601 Boehringer Ingelheim Investigational Site	Hillerød
Denmark	1222.14.4603 Boehringer Ingelheim Investigational Site	Roskilde
Finland	1222.14.4702 Boehringer Ingelheim Investigational Site	Espoo
Finland	1222.14.4701 Boehringer Ingelheim Investigational Site	HUS
Finland	1222.14.4703 Boehringer Ingelheim Investigational Site	Lohja
Germany	1222.14.4106 Boehringer Ingelheim Investigational Site	Aschaffenburg
Germany	1222.14.4112 Boehringer Ingelheim Investigational Site	Berlin
Germany	1222.14.4103 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	1222.14.4110 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	1222.14.4108 Boehringer Ingelheim Investigational Site	Gelnhausen
Germany	1222.14.4107 Boehringer Ingelheim Investigational Site	Kelkheim
Germany	1222.14.4114 Boehringer Ingelheim Investigational Site	Lübeck
Germany	1222.14.4111 Boehringer Ingelheim Investigational Site	Mainz
Germany	1222.14.4113 Boehringer Ingelheim Investigational Site	Minden
Germany	1222.14.4109 Boehringer Ingelheim Investigational Site	Mönchengladbach
Germany	1222.14.4104 Boehringer Ingelheim Investigational Site	Rodgau-Dudenhofen
Germany	1222.14.4105 Boehringer Ingelheim Investigational Site	Wiesloch
Hong Kong	1222.14.5501 Boehringer Ingelheim Investigational Site	Hong Kong
India	1222.14.5412 Boehringer Ingelheim Investigational Site	Coimbatore
India	1222.14.5406 Boehringer Ingelheim Investigational Site	Hyderabad
India	1222.14.5402 Boehringer Ingelheim Investigational Site	Indore
India	1222.14.5405 Boehringer Ingelheim Investigational Site	Jaipur
India	1222.14.5409 Boehringer Ingelheim Investigational Site	Jaipur
India	1222.14.5403 Boehringer Ingelheim Investigational Site	Mangalore
India	1222.14.5407 Boehringer Ingelheim Investigational Site	Mysore
India	1222.14.5404 Boehringer Ingelheim Investigational Site	Nagpur
India	1222.14.5408 Boehringer Ingelheim Investigational Site	Noida
India	1222.14.5401 Boehringer Ingelheim Investigational Site	Pune
India	1222.14.5410 Boehringer Ingelheim Investigational Site	Vellore
Italy	1222.14.4301 Boehringer Ingelheim Investigational Site	Cassano Delle Murge (ba)
Italy	1222.14.4302 Boehringer Ingelheim Investigational Site	Genova
Italy	1222.14.4304 Boehringer Ingelheim Investigational Site	Milano
Italy	1222.14.4305 Boehringer Ingelheim Investigational Site	Parma
Italy	1222.14.4303 Boehringer Ingelheim Investigational Site	Roma
Korea, Republic of	1222.14.5301 Boehringer Ingelheim Investigational Site	Bucheon
Korea, Republic of	1222.14.5302 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.14.5305 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.14.5306 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.14.5304 Boehringer Ingelheim Investigational Site	Uijeongbu
Korea, Republic of	1222.14.5303 Boehringer Ingelheim Investigational Site	Wonju
Malaysia	1222.14.5701 Boehringer Ingelheim Investigational Site	Georgetown, Pulau Pinang
Malaysia	1222.14.5703 Boehringer Ingelheim Investigational Site	Kuala Lumpur
Malaysia	1222.14.5702 Boehringer Ingelheim Investigational Site	Kuching, Sarawak
Norway	1222.14.4802 Boehringer Ingelheim Investigational Site	Fredrikstad
Norway	1222.14.4801 Boehringer Ingelheim Investigational Site	SKI
Philippines	1222.14.5802 Boehringer Ingelheim Investigational Site	Iloilo City
Philippines	1222.14.5803 Boehringer Ingelheim Investigational Site	Iloilo City
Philippines	1222.14.5801 Boehringer Ingelheim Investigational Site	Manila
Romania	1222.14.6103 Boehringer Ingelheim Investigational Site	Brasov
Romania	1222.14.6102 Boehringer Ingelheim Investigational Site	Constanta
Romania	1222.14.6101 Boehringer Ingelheim Investigational Site	Iasi
Russian Federation	1222.14.6203 Boehringer Ingelheim Investigational Site	Petrozavodsk
Russian Federation	1222.14.6201 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	1222.14.6202 Boehringer Ingelheim Investigational Site	St. Petersburg
South Africa	1222.14.4901 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	1222.14.4902 Boehringer Ingelheim Investigational Site	Cape Town
Spain	1222.14.4401 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1222.14.4402 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1222.14.4406 Boehringer Ingelheim Investigational Site	Madrid
Spain	1222.14.4405 Boehringer Ingelheim Investigational Site	Mérida
Spain	1222.14.4403 Boehringer Ingelheim Investigational Site	Palma de Mallorca
Spain	1222.14.4407 Boehringer Ingelheim Investigational Site	Terrassa (Barcelona)
Sweden	1222.14.4501 Boehringer Ingelheim Investigational Site	Boden
Sweden	1222.14.4503 Boehringer Ingelheim Investigational Site	Göteboerg
Sweden	1222.14.4502 Boehringer Ingelheim Investigational Site	Lund
Thailand	1222.14.5904 Boehringer Ingelheim Investigational Site	Bangkok
Thailand	1222.14.5901 Boehringer Ingelheim Investigational Site	Khon Kaen
Thailand	1222.14.5902 Boehringer Ingelheim Investigational Site	Songkla

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Argentina,  Brazil,  Canada,  Czech Republic,  Denmark,  Finland,  Germany,  Hong Kong,  India,  Italy,  Korea, Republic of,  Malaysia,  Norway,  Philippines,  Romania,  Russian Federation,  South Africa,  Spain,  Sweden,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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	No
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.	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.	No
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).	Baseline, Week 24	No
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).	Baseline, Week 24	No
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).	Baseline, Week 24	No
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).	Baseline, Week 48	No
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).	Baseline, Week 12	No
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.	Baseline, Week 24	No
Secondary	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 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.	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	No
Secondary	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 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.	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	No
Secondary	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 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.	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	No
Secondary	Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 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.	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	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Trough FEV1 Response 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.	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.	No
Secondary	Peak FEV1 (0-3h) Response 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.	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	No
Secondary	Peak FEV1 (0-3h) Response 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.	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	No
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.	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	No
Secondary	Peak FEV1 (0-3h) Response 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.	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	No
Secondary	Peak FEV1 (0-3h) Response 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.	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	No
Secondary	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 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.	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	No
Secondary	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 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.	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	No
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.	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	No
Secondary	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 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.	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	No
Secondary	Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 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.	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	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Trough FVC Response 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.	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.	No
Secondary	Peak FVC (0-3h) Response 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.	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	No
Secondary	Peak FVC (0-3h) Response 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.	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	No
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.	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	No
Secondary	Peak FVC (0-3h) Response 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.	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	No
Secondary	Peak FVC (0-3h) Response 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.	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	No
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.	Week 24	No
Secondary	Use of Rescue Medication at Week 24	Mean number of puffs of rescue medication used per day (daytime/nighttime/total)	Week 24	No
Secondary	Patient's Global Rating (PGR) at 6 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).	Week 6	No
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).	Week 12	No
Secondary	Patient's Global Rating (PGR) at 24 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).	Week 24	No
Secondary	Patient's Global Rating (PGR) at 48 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).	Week 48	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 6 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).	Baseline, Week 6	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 12 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).	Baseline, Week 12	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 18 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).	Baseline, Week 18	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 32 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).	Baseline, Week 32	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 40 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).	Baseline, Week 40	No
Secondary	Mahler Transitional Dyspnea Index Focal Score at 48 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).	Baseline, Week 48	No
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.	Baseline to end of study at 48 weeks.	No
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.	Baseline to end of study at 48 weeks.	No
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.	Baseline to end of study at 48 weeks.	No
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.	Baseline to end of study at week 48 visit	No
Secondary	Number of COPD Exacerbations Requiring 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.	Baseline to end of study at week 48 visit	No
Secondary	Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) 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. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids.	Baseline to end of study at 48 weeks.	No
Secondary	Changes in Safety Parameters Related to Treatment	Occurence of cardiac disorders and investigations related to treatment.	48 weeks	No
Secondary	Absolute Plasma Concentrations	Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means.	within 2 hours before first study drug administration and 10 minutes post-dose at week 6, 12 and 18	No

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