Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double Blind, Placebo Controlled, Incomplete Block, Crossover, Dose Ranging Study to Evaluate the Dose Response of GSK573719 Administered Once or Twice Daily Over 7 Days in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Brief Summary: The purpose of this study is to further characterize the dose response of GSK573719 at doses of 15.6 micrograms (mcg) to 125 mcg once daily in patients with chronic obstructive pulmonary disease (COPD). Treatment with doses of GSK573719 dosed twice daily will also be included to further evaluate dosing frequency. Treatment with tiotropium (18 mcg) once daily via the Handihaler will be included as an active control. A placebo treatment will be included in order to evaluate absolute treatment effect of the different doses of GSK573719.


Options:
A: Inclusion Criteria:

* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Japanese ethnic origin defined as having been born in Japan with four ethnic Japanese grandparents and able to speak Japanese.
* Male or female between 20 and 65 years of age inclusive, at the time of signing the informed consent.
* A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\].
* Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until completion of the follow-up visit.
* Body weight \> or equal to 45 kg and BMI within the range 18-28 kg/m2 inclusive.
* AST, ALT, alkaline phosphatase and bilirubin \< or equal to 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Average QTcB or QTcF \< 450 msec; or QTc \< 480 msec in subjects with Bundle Branch Block taken from triplicate assessments at screening.
* No clinically active and relevant abnormality on 12-lead ECG or 24h Holter ECG at screening.
* Normal spirometry (FEV1 ≥ 80% of predicted, FEV1/FVC ≥ 70%).
* Non-smokers (never smoked or not smoking for \>6 months with \<10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked))
* A signed and dated written informed consent is obtained from the subject
* The subject is capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form
* Available to complete the study

Exclusion Criteria:

* Any clinically important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead). A 24hr Holter monitoring recording outside normal limits.
* A history of breathing problems (i.e. history of asthmatic symptomatology, unless asthma in childhood that has now resolved and no longer requires maintenance therapy which should not be an exclusion).
* A mean QTc(B) value at screening \>450msec, or an ECG that is not suitable for QT measurements (e.g. LBBB or poorly defined termination of the T wave).
* A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening.
* A mean heart rate outside the range 40-90 bpm at screening.
* The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates and benzodiazepines. The detection of drugs with a legitimate medical use would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
* A positive test for HIV antibody.
* History of regular alcohol consumption within 3months of the study defined as:

an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). Under Australian guidelines, one standard unit defined as 10g of ethanol, is equivalent to 250ml of full-strength beer, 470 ml of light-strength beer, 100 ml of wine and 30ml of spirits.

* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Unwillingness or inability to follow the procedures outlined in the protocol. 17. Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products prior to screening.
* The subject is unable to use the novel dry powder inhaler correctly.
* The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium, atropine and any of its derivatives.
* Any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug.
* The subject has a known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and MgSt.
* Subject is kept under regulatory of judicial order in an institution.
* Any female of childbearing potential.
* Subject is mentally or legally incapacitated.
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 greater than or equal to 35% and less than or equal to 80% of predicted normal

Exclusion Criteria:

* Pregant or lactating women or women planning to become 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
* abnormal and clinically significant Holter monitor finding at Visit 1
* significantly abnormal finding from laboratory tests at Visit 1
* unable to withhold albuterol/salbutamol and/or ipratropium bromide 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 within 6 weeks of Visit 1
* use of anitbiotics for lower respiratory tract infection within 6 weeks of Visit 1
* use of cytochrome P450 3A4 inhibitors within 6 weeks of Visit 1
* us of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) products if LABA/ICS therapy is discontinued completely within 30 days of Visit 1
* use of ICS at a dose of \>10000mcg/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 within 14 days of Visit 1
* use of roflumilast within 14 days of Visit 1
* use of theophyllines within 48 hours of Visit 1
* use of oral leukotriene inhibitors within 48 hours prior to Visit 1
* use of long-acting oral beta-agonists within 48 hours of Visit 1
* use of short-acting oral beta-agonists within 12 hours of Visit 1
* use of inhaled long-acting beta-agonists within 48 hours prior to 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 within 4 hours of Visit 1
* use of inhaled short-acting anticholinergics within 4 hours of Visit 1
* use of inhaled short-acting anticholinergic/short-acting beta2-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) of Visit 1
* long-term oxygen therapy prescribed for \>12 hours per day
* regular use of short-acting bronchodilators
* use of CPAP or NIPPV
* participation in the maintenance phase of a pulmonary rehabilitation program
* known or suspected history of alcohol or drug abluse with 2 years prior to Visit 1
* anyone affiliated with the investigator site (e.g., investigator, study coordinator, etc.)
* previous use of GSK573719, GW642444 , GSK573719/GW642444 combination, GSK233705/GW642444 combination, or Fluticasone Furoate/GW642444 combination
C: 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
D: Inclusion Criteria:

* Diagnosis of COPD
* 10 pack-year or greater history of cigarette smoking
* Post-bronchodilator FEV1/FVC of \<0.7
* Predicted FEV1 of 70% of normal or less
* Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

Exclusion Criteria:

* Women who are pregnant, lactating, or planning to become pregnant
* Respiratory disorders other than COPD, including a current diagnosis of asthma
* Clinically significant non-respiratory diseases or abnormalities that are not adequate controlled
* Significant allergy or hypersensitivity to anticholinergics, beta-agonist, or the excipients of magnesium stereate or lactose used in the inhaler delivery device
* Hospitalization for COPD or pneumonia within 12 weeks prior to screening
* Lung volume reduction surgery within 12 weeks prior to screening
* Abnormal and clinically significant ECG findings at screening
* Clinically significant laboratory findings at screening
* Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (\>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit
* Use of long-term oxygen therapy (12 hours or greater per day)
* Regular use of nebulized treatment with short-acting bronchodilators
* Participation in the acute phase of a pulmonary rehabilitation program
* A know or suspected history of alcohol or drug abuse
* Affiliation with the investigational site
* Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW64244

Answer: C