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

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: NCT00793624
• Other study ID #: 1222.13
• Secondary ID: 2008-001933-84
• Status: Completed
• Phase: Phase 3
• First received: November 18, 2008
• Last updated: June 17, 2014
• Start date: February 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: Therapeutic Products DirectorateCroatia: Croatian Institute for Medicines Control, HR-10000 ZagrebCzech 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 per la sperim. clinica dei medicinali dell'A.O. Universitaria Pisana di PisaKorea, Republic of: Korea Food and Drug AdministrationMalaysia: Ministry of HealthNorway: Norwegian Medicines Agency (Statens Legemiddelverk)Philippines: Department of HealthSouth Africa: Medicines Control CouncilSpain: Agencia Espanola del Medicamento y Productos SanitariosSweden: Medical Products Agency Regional Ethics Committee of UmeåThailand: Ministry of Public HealthUkraine: Ministry of Health Care of Ukraine (MoH of Ukraine)
• 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: 906
• 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 for comparison with Olodaterol (BI 1744) on safety and efficacy in COPD patients
• Placebo
Placebo for comparison Formoterolon safety and efficacy in COPD patients

Locations

Country	Name	City	State
Argentina	1222.13.2401 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1222.13.2403 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1222.13.2402 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	1222.13.2404 Boehringer Ingelheim Investigational Site	Monte Grande
Brazil	1222.13.2502 Boehringer Ingelheim Investigational Site	Juiz de Fora
Brazil	1222.13.2503 Boehringer Ingelheim Investigational Site	Rio de Janeiro
Brazil	1222.13.2505 Boehringer Ingelheim Investigational Site	Rio de Janeiro
Brazil	1222.13.2501 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	1222.13.2504 Boehringer Ingelheim Investigational Site	Sao Paulo
Canada	1222.13.1408 Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	1222.13.1407 Boehringer Ingelheim Investigational Site	Chilliwack	British Columbia
Canada	1222.13.1403 Boehringer Ingelheim Investigational Site	Downsview	Ontario
Canada	1222.13.1412 Boehringer Ingelheim Investigational Site	Hamilton	Ontario
Canada	1222.13.1404 Boehringer Ingelheim Investigational Site	La Malbaie	Quebec
Canada	1222.13.1411 Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	1222.13.1401 Boehringer Ingelheim Investigational Site	Niagara Falls	Ontario
Canada	1222.13.1406 Boehringer Ingelheim Investigational Site	Point Claire	Quebec
Canada	1222.13.1410 Boehringer Ingelheim Investigational Site	Sarnia	Ontario
Canada	1222.13.1402 Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan
Canada	1222.13.1413 Boehringer Ingelheim Investigational Site	Toronto	Ontario
Croatia	1222.13.3502 Boehringer Ingelheim Investigational Site	Dubrovnik
Croatia	1222.13.3503 Boehringer Ingelheim Investigational Site	Rijeka
Croatia	1222.13.3504 Boehringer Ingelheim Investigational Site	Split
Croatia	1222.13.3501 Boehringer Ingelheim Investigational Site	Zagreb
Czech Republic	1222.13.3401 Boehringer Ingelheim Investigational Site	Beroun
Czech Republic	1222.13.3403 Boehringer Ingelheim Investigational Site	Cesky Tesin
Czech Republic	1222.13.3402 Boehringer Ingelheim Investigational Site	Tabor
Denmark	1222.13.2003 Boehringer Ingelheim Investigational Site	Aalborg
Denmark	1222.13.2002 Boehringer Ingelheim Investigational Site	Hvidovre
Denmark	1222.13.2001 Boehringer Ingelheim Investigational Site	Silkeborg
Finland	1222.13.2103 Boehringer Ingelheim Investigational Site	Lahti
Finland	1222.13.2101 Boehringer Ingelheim Investigational Site	Tampere
Finland	1222.13.2102 Boehringer Ingelheim Investigational Site	Turku
Germany	1222.13.1502 Boehringer Ingelheim Investigational Site	Berlin
Germany	1222.13.1503 Boehringer Ingelheim Investigational Site	Berlin
Germany	1222.13.1506 Boehringer Ingelheim Investigational Site	Berlin
Germany	1222.13.1511 Boehringer Ingelheim Investigational Site	Dortmund
Germany	1222.13.1514 Boehringer Ingelheim Investigational Site	Essen
Germany	1222.13.1509 Boehringer Ingelheim Investigational Site	Großhansdorf
Germany	1222.13.1508 Boehringer Ingelheim Investigational Site	Hannover
Germany	1222.13.1510 Boehringer Ingelheim Investigational Site	Hannover
Germany	1222.13.1512 Boehringer Ingelheim Investigational Site	Kiel
Germany	1222.13.1501 Boehringer Ingelheim Investigational Site	Köln
Germany	1222.13.1505 Boehringer Ingelheim Investigational Site	Reinfeld
Germany	1222.13.1507 Boehringer Ingelheim Investigational Site	Schwerin
Hong Kong	1222.13.2901 Boehringer Ingelheim Investigational Site	Kowloon
India	1222.13.2804 Boehringer Ingelheim Investigational Site	Bangalore
India	1222.13.2803 Boehringer Ingelheim Investigational Site	Chennai
India	1222.13.2806 Boehringer Ingelheim Investigational Site	Coimbatore-
India	1222.13.2810 Boehringer Ingelheim Investigational Site	Hyderabad
India	1222.13.2801 Boehringer Ingelheim Investigational Site	Indore
India	1222.13.2807 Boehringer Ingelheim Investigational Site	Indore
India	1222.13.2805 Boehringer Ingelheim Investigational Site	Jaipur
India	1222.13.2802 Boehringer Ingelheim Investigational Site	Ludhiana, Punjab
India	1222.13.2809 Boehringer Ingelheim Investigational Site	Mumbai
India	1222.13.2812 Boehringer Ingelheim Investigational Site	Mumbai
India	1222.13.2811 Boehringer Ingelheim Investigational Site	Pune
Italy	1222.13.1704 Boehringer Ingelheim Investigational Site	Catania
Italy	1222.13.1702 Boehringer Ingelheim Investigational Site	Genova
Italy	1222.13.1701 Boehringer Ingelheim Investigational Site	Pisa
Italy	1222.13.1705 Boehringer Ingelheim Investigational Site	Siena
Italy	1222.13.1703 Boehringer Ingelheim Investigational Site	Trieste
Korea, Republic of	1222.13.2701 Boehringer Ingelheim Investigational Site	Gwangju
Korea, Republic of	1222.13.2702 Boehringer Ingelheim Investigational Site	Incheon
Korea, Republic of	1222.13.2703 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.13.2705 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.13.2706 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1222.13.2704 Boehringer Ingelheim Investigational Site	Suwon
Malaysia	1222.13.3103 Boehringer Ingelheim Investigational Site	Batu Caves
Malaysia	1222.13.3101 Boehringer Ingelheim Investigational Site	Kota Kinabalu
Malaysia	1222.13.3102 Boehringer Ingelheim Investigational Site	Kuala Lumpur
Malaysia	1222.13.3104 Boehringer Ingelheim Investigational Site	Kuantan
Norway	1222.13.2201 Boehringer Ingelheim Investigational Site	Bergen
Norway	1222.13.2202 Boehringer Ingelheim Investigational Site	Oslo
Philippines	1222.13.3203 Boehringer Ingelheim Investigational Site	Cebu
Philippines	1222.13.3201 Boehringer Ingelheim Investigational Site	Quezon City
Philippines	1222.13.3202 Boehringer Ingelheim Investigational Site	Quezon City
South Africa	1222.13.2302 Boehringer Ingelheim Investigational Site	Durban
South Africa	1222.13.2301 Boehringer Ingelheim Investigational Site	Pretoria
Spain	1222.13.1803 Boehringer Ingelheim Investigational Site	Aranjuez
Spain	1222.13.1806 Boehringer Ingelheim Investigational Site	Elda
Spain	1222.13.1802 Boehringer Ingelheim Investigational Site	Els Hostalets de Balenyà
Spain	1222.13.1804 Boehringer Ingelheim Investigational Site	Pozuelo de Alarcón
Spain	1222.13.1805 Boehringer Ingelheim Investigational Site	Valladolid
Spain	1222.13.1801 Boehringer Ingelheim Investigational Site	Vic (Barcelona)
Sweden	1222.13.1901 Boehringer Ingelheim Investigational Site	Boden
Sweden	1222.13.1902 Boehringer Ingelheim Investigational Site	Sundsvall
Thailand	1222.13.3302 Boehringer Ingelheim Investigational Site	Bangkok
Thailand	1222.13.3303 Boehringer Ingelheim Investigational Site	Bangkok
Thailand	1222.13.3301 Boehringer Ingelheim Investigational Site	Chiang Mai
Ukraine	1222.13.3602 Boehringer Ingelheim Investigational Site	Ivano-Frankivsk
Ukraine	1222.13.3601 Boehringer Ingelheim Investigational Site	Kharkiv
Ukraine	1222.13.3603 Boehringer Ingelheim Investigational Site	Kiev

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

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

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 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 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 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 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	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	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	Absolute Plasma Concentrations	Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means.	within 2 hours before first drug administration and 10 minutes post-dose at week 6, 12 and 18	No
Secondary	Changes in Safety Parameters Related to Treatment	Occurence of cardiac disorders and investigations related to treatment.	48 weeks	No

External Links

•   Link