Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Trial Comparing the Efficacy and Safety of Umeclidinium/Vilanterol 62.5/25 mcg Once Daily With Tiotropium 18 mcg Once Daily Over 24 Weeks in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Brief Summary: The purpose of this 24 week study is to evaluate the spirometric lung function effect (trough FEV1) of Umeclidinium/Vilanterol 62.5/25 once daily compared to Tiotropium 18 mcg once daily along with safety assessments in subjects with COPD.


Options:
A: Inclusion Criteria:

* Type of subject: Outpatient.
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Age: Subjects 40 years of age or older at Visit 1.
* Gender: Male and female subjects are eligible to participate in the study. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g., age appropriate, \>45 years, in the absence of hormone replacement therapy. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact): Abstinence; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS) that meets the Standard Operating Procedure (SOP) effectiveness criteria as stated in the product label; Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
* Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society
* Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack year history.
* Severity of Disease: A pre and post-albuterol/salbutamol Forced Expiratory Volume in One Second /Forced Vital Capacity (FEV1/FVC) ratio of \<0.70 and post-albuterol/salbutamol FEV1 of \<=70% of predicted normal values at Visit 1 (Screening) calculated using reference values provided by Quanjer.
* Current clinically prescribed medication: The subject must be on the dose and frequency of one of the following ICS/LABA combinations approved for COPD at least 30 days prior screening : FSC at a dose of 500/50 mcg twice-daily (i.e. SERETIDE DISKUS™ inhaler or approved generic product such as AIRFLUSAL FORSPIRO inhaler 500/50 mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50 mcg twice daily) ; The combination of budesonide/formoterol (i.e., SYMBICORT TURBUHALER inhaler) at doses of 200/6 mcg twice-daily or 400/12 mcg twice-daily .
* Dyspnea: A score of \>=2 on the Modified Medical Research Council (mMRC) Dyspnea Scale at Visit 1.

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: A current diagnosis of asthma.
* Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease.
* Other Diseases/Abnormalities: The subject is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediately life-threatening illness e.g. cancer.
* Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, corticosteroid (intranasal, inhaled or systemic) lactose/milk protein or magnesium stearate.
* Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1.
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1.
* Unstable or life threatening cardiac disease: UMEC should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV heart failure
* 12-Lead Electrocardiogram (ECG): Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Principle Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study: Atrial fibrillation with rapid ventricular rate \>120 beats per minute (bpm); Sustained or nonsustained ventricular tachycardia; Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted)
* Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.
* Interactions: Concomitant administration with beta-blockers and strong Cytochrome P450 3A4 (CYP3A4) inhibitors is only permitted if, in the Investigator's opinion, the likely benefit outweighs the potential risk.
* Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.
* Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
* Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids (12 weeks), Systemic, oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract infection) (6 weeks); CYP3A4 strong inhibitors (6 weeks) ; ICS /LABA combination products except SERETIDE and approved FSC 500/50 generic products and SYMBICORT at approved doses and frequencies for COPD (30 days) ; SERETIDE, approved FSC 500/50 generic products, and SYMBICORT at approved doses and frequencies for COPD (12 hours prior to screening); Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) (14 days); Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, UMEC) (7 days); Inhaled long acting beta2 agonists (LABA) (salmeterol, formoterol: 48 hrs) olodaterol, indacaterol (14 days); LAMA/LABA combination products (Apply whichever mono component has the longest washout) Theophyllines (48 hours); Oral beta2-agonists (Long-acting: 48 hours) (Short-acting: 12 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergics (4 hours); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (4 hours); Any other investigational medication (30 days or within 5 drug half-lives, whichever is longer). Note: Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing. Intra-articular and epidural corticosteroid injections are permitted. Corticosteroids for short term treatment of COPD exacerbations is allowed
* Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \<=12 hours per day) is not exclusionary.
* Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1, or who will enter the acute phase of a pulmonary rehabilitation program during the study. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
* Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
* Affiliation with Investigator Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator, study coordinator, or employee of the participating investigator.
* Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete a questionnaire.

DISKUS is a trade mark of the GlaxoSmithKline Group of Companies. Other company or product names mentioned herein may be the property of their respective owners.
B: Inclusion Criteria:

* Type of subject: Outpatient.
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Age: Subjects 40 years of age or older at Visit 1.
* Gender: Male or female subjects.

A female is eligible to enter and participate in the study if she is of:

Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, \> 45 years, in the absence of hormone replacement therapy.

OR

Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact):

* Abstinence
* Oral Contraceptive, either combined or progestogen alone
* Injectable progestogen
* Implants of levonorgestrel
* Estrogenic vaginal ring
* Percutaneous contraceptive patches
* Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label
* Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records.
* Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

  * COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\].
  * Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

Note: Pipe and/or cigar use cannot be used to calculate pack-year history

* Severity of Disease: A pre and post-albuterol/salbutamol FEV1/FVC ratio of \<0.70 and a pre and post-albuterol/salbutamol FEV1 of FEV1 of \<=70% of predicted normal values calculated using NHANES III reference equations at Visit 1 \[Hankinson, 1999; Hankinson, 2010\].
* Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: A current diagnosis of asthma.
* Other Respiratory Disorders: Known alpha 1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease.
* Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for \<5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
* Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
* Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
* 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead electrocardiogram (ECG) which causes the underlying rhythm and ECG to be obscured. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. Specific ECG findings that preclude subject eligibility are listed in Appendix 4. The study investigator will determine the medical significance of any ECG abnormalities not listed in Appendix 4.
* Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
* Use of certain medications according to defined time intervals prior to Screening (Visit 1).
* Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \>=12 hours per day) is not exclusionary.
* Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
* Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
* Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
* Previous use of study drug: Previous participation in DB2113360 or DB2113374.
C: Inclusion Criteria:

* Outpatient.
* A signed and dated written informed consent prior to study participation.
* Japanese subjects 40 years of age or older at Visit 1.
* Male or female subjects. A female is eligible if she is of: Non-child bearing potential or Child bearing potential agrees to one of the contraceptive methods.
* Subjects with a clinical history of COPD in accordance with the definition by COPD domestic guideline.
* Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years at Visit 1.
* Subject with a measured post-salbutamol forced expiratory volume/forced vital capacity (FEV1/FVC) ratio of \<70% and Subjects with a measured post-salbutamol FEV1 \<80% of predicted normal values.

Exclusion Criteria (Visit 1):

* Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* A current diagnosis of asthma.
* Known respiratory disorders other than COPD.
* Subjects with historical or current evidence of clinically significant abnormalities that are uncontrolled.
* A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD.
* Allergy or hypersensitivity to muscarinic, beta2-agonist, lactose/milk protein or magnesium stearate or a condition that contraindicates participation.
* Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
* Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
* An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1.
* Significantly abnormal finding from clinical chemistry or hematology, tests at Visit 1.
* Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day.
* Regular use (prescribed every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol) via nebulized therapy.
* Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1.
* A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
* Affiliation with Investigator Site.
* Previous use of GSK573719, the GSK573719/GW642444 combination.
* Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer).

Exclusion Criteria (Visit 2):

- COPD Exacerbation during run-in period: Subject must not have experienced a COPD exacerbation or a lower respiratory tract infection during run-in or at Visit 2.
D: Inclusion Criteria:

* Outpatient
* A signed and dated written informed consent prior to study participation.
* Male or female adults.
* 40 to 80 years of age at Visit 1
* Diagnosis of COPD
* Current or former cigarette smokers with a history of cigarette smoking of greater than or equal to 10 pack-years
* Post-albuterol forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC)\<0.70 and post albuterol FEV1 of greater than or equal to 35% and less than or equal to 70% of predicted normal values

Exclusion Criteria:

* Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* A current diagnosis of asthma
* Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer
* Other significant respiratory conditions in addition to COPD
* Other diseases that are uncontrolled including cancer in remission for less than 5 years
* Chest x-ray or CT scan with clinically significant abnormalities not believed to be due to the presence of COPD
* Hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate
* A medical condition that contraindicates study participation or use of an inhaled anticholinergic
* Hospitalization for COPD or pneumonia within 12 weeks of Visit 1
* Any previous lung resection surgery
* A body mass index (BMI) value of \>35 kilogram (kg)/meter squared (m2)
* An abnormal and significant electrocardiogram finding at Visit 1
* Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1.
* A positive Hepatitis B surface antigen or positive Hepatitis C antibody
* Medically unable to withhold albuterol (salbutamol) for the 6 hour period prior to study visits
* Use of depot corticosteroids within 12 weeks of Visit 1
* Use of oral or parenteral corticosteroids or antibiotics for lower respiratory tract infection within 6 weeks of Visit 1
* Use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued within 30 days of Visit 1
* Use of ICS at a dose of \>1000mcg/day of fluticasone propionate or equivalent within 30 days of Visit 1
* Initiation or discontinuation of ICS within 30 days of Visit 1
* Use of tiotropium or phosphodiesterase 4 inhibitors within 14 days of Visit 1
* Use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or inhaled long-acting beta-agonists within 48 hours of Visit 1
* Short-acting oral beta-agonists within 12 hours of Visit 1
* Use of LABA/ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy within 48 hours of Visit 1 for the LABA component
* Use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1
* Use of inhaled short-acting beta-agonists, inhaled short-acting anticholinergics, or inhaled short-acting anticholinergic/short-acting beta-agonist combination products within 6 hours of Visit 1
* Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer)
* Oxygen therapy prescribed for greater than 12 hours a day
* Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators
* Use of continuous positive airway pressure (CPAP), nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV), including use for sleep apnea.
* Acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1
* A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1
* Anyone affiliated with investigator site
* Previous use of GSK573719 or GSK53719/GW642444

Answer: B