Co-administration of Olodaterol Respimat® and Tiotropium... | NCT01694771

Label	Type	Description	Intervention Names
Olodaterol and Tiotropium	Experimental	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered	Drug: Olodaterol Drug: Tiotropium
Placebo and Tiotropium	Other	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered	Drug: Tiotropium Drug: Placebo matching Olodaterol

Name	Type	Description	Arm Group Labels	Other Names
Tiotropium	Drug	Marketed dose	Placebo and Tiotropium
Placebo matching Olodaterol

Measure	Description	Time Frame
FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12	FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12	baseline and 12 weeks
Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12	Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12	baseline and 12 weeks

Measure	Description	Time Frame
Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline	Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline	baseline and 12 weeks
FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline

Eligibility Module

Eligibility Criteria

Inclusion criteria:

All patients must sign an informed consent consistent with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.
All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have a relatively stable airway obstruction with a post-bronchodilator FEV1 = 30 % and < 80% of predicted normal and a post-bronchodilator FEV1/FVC <70% at Visit 1.
Male or female patients, 40 years of age or older.
Patients must be current or ex-smokers with a smoking history of more than 10 pack years
Patients must be able to: perform technically acceptable pulmonary function tests, and maintain records(paper diary).
Patients must be able to inhale medication in a competent manner from the Respimat Inhaler as well as the Handihaler.

Exclusion criteria:

Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patients ability to participate in the study.
Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST >x2 ULN, ALT >x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients).
Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count =600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition.
A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists).
A history of myocardial infarction within 1 year of screening visit (Visit 1).
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 (patients with treated basal cell carcinoma are allowed).
A history of life-threatening pulmonary obstruction.
A history of cystic fibrosis.
Clinically evident bronchiectasis.
A history of significant alcohol or drug abuse.
Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1).
Patients being treated with oral or patch ß-adrenergics.
Patients being treated with 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.
Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits.
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.
Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1).
Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution.
Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler®.
Pregnant or nursing women.
Women of childbearing potential not using a highly effective method of birth control*. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.

* as per ICH M3(R2) a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year).
Patients who have previously been randomised in this study or are currently participating in another study.
Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
1222.51.01055 Boehringer Ingelheim Investigational Site		Florence	Alabama		United States
1222.51.01087 Boehringer Ingelheim Investigational Site

PubMed Identifier	Type	Citation	Retractions
25342898	Derived	ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R. Efficacy and safety of combining olodaterol Respimat((R)) and tiotropium HandiHaler((R)) in patients with COPD: results of two randomized, double-blind, active-controlled studies. Int J Chron Obstruct Pulmon Dis. 2014 Oct 14;9:1133-44. doi: 10.2147/COPD.S72482. eCollection 2014.

ID	Title	Description
FG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose Tiotropium: Marketed dose
FG001	Placebo and Tiotropium (18µg)

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12

FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12

Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks. FAS included all patients in the treated set who had both baseline and at least one post-baseline measurement at or before 12 weeks for any of the co-primary efficacy variables

Posted

Least Squares Mean

Standard Error

Area Under the Curve (L)

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants	OG000563 OG001564

Title

Denominators

Categories

Title	Measurements
	OG0000.313± 0.010 OG0010.196± 0.010

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (564), Tio+Olo 5ug (563).	Mixed Model Repeated Measure		<0.0001		Mean Difference (Final Values)	0.117	Standard Error of the Mean	0.014	2-Sided	95	0.090	0.144				No	Superiority or Other

Primary

Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12

Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12

Full Analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.

Posted

Least Squares Mean

Standard Error

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants

Secondary

Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline

Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline

Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.

Posted

Least Squares Mean

Standard Error

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants

Secondary

FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline

Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.

Posted

Least Squares Mean

Standard Error

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants

Secondary

Trough FVC Response at 12 Weeks- Defined as Change From Baseline

Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation

Posted

Least Squares Mean

Standard Error

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants

Secondary

Peak FVC Response at 12 Weeks - Defined as Change From Baseline

Peak FVC response at 12 weeks - defined as change from baseline.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.

Posted

Least Squares Mean

Standard Error

baseline and 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Units	Counts
Participants

Secondary

Rescue Medication Usage - Percentage of Rescue Free Days

Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).

Full analysis set (FAS) with last observation carried forward (LOCF) imputation

Posted

Least Squares Mean

Standard Error

percentage of days

over 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Secondary

Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)

Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation

Posted

Least Squares Mean

Standard Error

usage (total daily) number of puffs

over 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Secondary

Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)

Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation

Posted

Least Squares Mean

Standard Error

percentage of days

over 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Secondary

Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)

Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.

Full analysis set (FAS) with last observation carried forward (LOCF) imputation

Posted

Least Squares Mean

Standard Error

percentage of days

over 12 weeks

ID	Title	Description
OG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
OG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute myocardial infarction	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Atrial fibrillation	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Atrial flutter	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Cardiac failure congestive	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0002 affected567 at risk EG0012 affected565 at risk
Myocardial infarction	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0002 affected567 at risk EG0011 affected565 at risk
Myocardial ischaemia	Cardiac disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Gastritis	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Ileus	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Intestinal ischaemia	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Intestinal obstruction	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Obstruction gastric	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Oesophagitis	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Rectal haemorrhage	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Volvulus	Gastrointestinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Chest pain	General disorders	MEDDRA 16.0	Systematic Assessment	EG0002 affected567 at risk EG0011 affected565 at risk
Cholelithiasis	Hepatobiliary disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Bronchitis	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Campylobacter gastroenteritis	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Cellulitis	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Gastroenteritis	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0011 affected565 at risk
Groin infection	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Haemophilus infection	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Influenza	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Pneumonia	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0003 affected567 at risk EG0011 affected565 at risk
Pneumonia necrotising	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Post procedural infection	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Urinary tract infection	Infections and infestations	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Arthropod bite	Injury, poisoning and procedural complications	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Chest injury	Injury, poisoning and procedural complications	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Post procedural haematoma	Injury, poisoning and procedural complications	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Dehydration	Metabolism and nutrition disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Hypokalaemia	Metabolism and nutrition disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Hyponatraemia	Metabolism and nutrition disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Intraductal proliferative breast lesion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Lung cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Oesophageal carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Haemorrhagic cerebral infarction	Nervous system disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Loss of consciousness	Nervous system disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Presyncope	Nervous system disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Vascular encephalopathy	Nervous system disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Anxiety	Psychiatric disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0011 affected565 at risk
Mental status changes	Psychiatric disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Nephrolithiasis	Renal and urinary disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Renal failure acute	Renal and urinary disorders	MEDDRA 16.0	Systematic Assessment	EG0002 affected567 at risk EG0010 affected565 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MEDDRA 16.0	Systematic Assessment	EG0003 affected567 at risk EG0010 affected565 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MEDDRA 16.0	Systematic Assessment	EG00014 affected567 at risk EG0019 affected565 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Pulmonary hypertension	Respiratory, thoracic and mediastinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0011 affected565 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Aortic aneurysm	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0002 affected567 at risk EG0010 affected565 at risk
Arteriosclerosis	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Haemorrhage	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Hypertensive crisis	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Peripheral arterial occlusive disease	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0000 affected567 at risk EG0011 affected565 at risk
Peripheral artery stenosis	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk
Peripheral vascular disorder	Vascular disorders	MEDDRA 16.0	Systematic Assessment	EG0001 affected567 at risk EG0010 affected565 at risk

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D009930	Organic Chemicals
D000470	Alkaloids
D006571	Heterocyclic Compounds
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring

ID	Title	Description
BG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose Tiotropium: Marketed dose
BG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Olodaterol (5µg) and Tiotropium (18µg)	2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Olodaterol: One dose, 2 inhalations once daily in the morning Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning			40	567	60	567
EG001	Placebo and Tiotropium (18µg)	2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning			26	565	52	565