Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-center Trial Comparing the Efficacy and Safety of GSK573719/GW642444 With GSK573719 and With Tiotropium Over 24 Weeks in Subjects With COPD
Brief Summary: This is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of two doses of GSK573719/GW642444 Inhalation Powder, GSK573719 Inhalation Powder via a Novel Dry Powder Inhaler and tiotropium via HandiHaler when administered once-daily over a 24-week treatment period in subjects with chronic obstructive pulmonary disease (COPD). Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to10 day run-in period followed by a randomization visit (Visit 2) then a 24-week treatment period. There will be a total of 9 clinic study visits. A follow-up phone contact for adverse event assessment will be conducted approximately one week after the last study visit (Visit 9 or Early Withdrawal). The total duration of subject participation in the study will be approximately 26 weeks. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, and clinical laboratory tests.


Options:
A: 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.
B: Inclusion Criteria:

* outpatient
* signed and dated written informed consent
* 40 years of age or older
* male and female subjects
* COPD diagnosis
* at least 10 pack-year smoking history
* post-albuterol/salbutamol FEV1/FVC ratio of \<0.70 and post-albuterol/salbutamol FEV1 of less than or equal to 70% predicted normal values
* score of greater than or equal to 2 on the Modified Medical Resarch Council Dyspnea Scale (mMRC)

Exclusion Criteria:

* women who are pregnant or lactating or are planning on becoming pregnant during the study
* current diagnosis of asthma
* other respiratory disorders other than COPD
* other diseases/abnormalities that are uncontrolled including cancer not in remission for at least 5 years
* chest x-ray or CT scan with clinically significant abnormalities not believed to be due to COPD
* hypersensitivity to anticholinergics, beta-agonists, lactose/milk protein or magnesium stearate or medical conditions associated with inhaled anticholinergics
* hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1
* lung volume reduction surgery within 12 months prior to Visit 1
* abnormal and clinically significant ECG at Visit 1
* significantly abnormal finding from laboratory tests at Visit 1
* unable to withhold albuterol/salbutamol at least 4 hours prior to spirometry at each visit
* use of depot corticosteroids within 12 weeks of Visit 1
* use of oral or parenteral corticosteroids, antibiotics for lower respiratory tract infection, or cytochrome P450 3A4 inhibitors, within 6 weeks of Visit 1
* use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued withing 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 roflumilast 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 4 hours of Visit 1
* use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer)
* long-term oxygen therapy prescribed for \>12 hours per day
* regular use of nebulized short-acting bronchodilators
* participation in acute phase of pulmonary rehabilitation program
* known or suspected history of alcohol or drug abse within 2 years prior to Visit 1
* anyone affiliated with the investigator site (e.g., investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member)
* previous exposure to GSK573719, GSK573719/GW642444 combination, GW642444 (vilanterol), or fluticasone furoate/GW642444 combination
C: Inclusion Criteria:

* Type of subject: Outpatient
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Participants 40 years of age or older at Visit 1.
* Gender: Male or female participants. 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. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
* 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 a pre and post-albuterol/salbutamol FEV1 of \<=70% predicted normal value at Visit 1, calculated using Quanjer reference equations.
* Dyspnoea: A score of \>= 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.
* QT interval corrected (QTc) Criteria: QTc \<450 milliseconds (msec) or QTc \<480 msec for patients with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The QTc should be based on single or averaged QTc values of triplicate Electrocardiogram (ECGs) obtained over a brief recording period.
* French participants: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

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. Allergy rhinitis is not exclusionary.
* Other Diseases/Abnormalities: Participants 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 or beta 2 agonist.
* Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lung Resection: Participants 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. Specific ECG findings that preclude subject eligibility will be listed in protocol The study investigator will determine the medical significance of any ECG abnormalities not listed.
* Screening labs: Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1 as determined by the study investigator.
* 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); Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g. fluticasone/salmeterol, mometasone, furoate/formoterol fumarate, budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30 days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of ICS at a dose \>1000 mcg/day of fluticasone propionate or equivalent (30 days); Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14 days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono component has the longest washout); Roflumilast (14 days); Oral beta-agonists- Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist \[SAMA\]) products eg ipratropium (4 hours); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting beta2-agonists \[SABA\]) (4 hours); Any other investigational medication (30 days or within 5 drug half-lives)
* Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy prescribed for greater than 12 hours per 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 12 weeks prior to Visit 1. Participants 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.
* 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.
* Participants who are pre-screen or screen failures cannot be re-screened.
D: 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, eg, 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 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.
* Diagnosis: an established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society (ERS)
* Smoking history: current or former cigarette smokers with a history of cigarette smoking of \>= 10 pack-years \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (eg. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)\]. 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 a post-albuterol/salbutamol FEV1 of \>=30% and =\<70% of predicted normal values at Visit 1. Predicted values will be based upon the ERS Global Lung Function Initiative
* 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: any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition (e.g. neurological condition) that is likely to affect respiratory function should not be included in the study.
* 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.
* Severe renal impairment: patients with severe renal impairment (e.g., end-stage renal disease requiring dialysis) should be excluded, unless in the opinion of the investigator, the benefit is likely to outweigh the risk.
* Unstable or life threatening cardiac disease: long-acting muscarinic antagonists (LAMA) 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
* Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/ muscarinic receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
* Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.
* Hospitalization: hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lung resection: lung volume reduction surgery within the 12 months prior to Visit 1.
* 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 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; sustained or nonsustained ventricular tachycardia; second degree heart block Mobitz type II or third degree heart block (unless pacemaker or defibrillator had been inserted)
* 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, inhaled long acting beta2 agonists/ inhaled corticosteroid (LABA/ICS) combination products if LABA/ICS therapy is discontinued completely 30 days; LABA/ICS combination products only If discontinuing ICS/ LABA therapy and switching to ICS monotherapy 48 hours for the salmeterol or formoterol component 14 days for the vilanterol component (note: the dose of ICS must be a dose of fluticasone propionate (FP) or equivalent but not to exceed 1000 mcg/day), use of ICS at a dose \>1000 microgram (mcg)/day of FP or equivalent 30 days (note: use of ICS is permitted provided the dose does not exceed 1000 mcg of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in the table above and switch to ICS monotherapy); initiation or discontinuation of ICS use 30 days (note: use of ICS is permitted provided the dose does not exceed 1000 mcg of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in the table above and switch to ICS monotherapy); phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) 14 days; LABA: salmeterol and formoterol 48 hours; olodaterol, indacaterol, and vilanterol 14 days; LAMA: tiotropium, aclidinium, glycopyrronium, umeclidinium 7 days; LAMA/LABA combination products if LAMA/LABA therapy is discontinued completely then 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 (note: use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing); 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).
* 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.
* 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

Answer: B