Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open Label, Randomised, Four-Period Crossover, Single Dose Study in Healthy Volunteers to Evaluate the Pharmacokinetics of FF/UMEC/VI Combination Administered at Dose Levels 100/62.5/25 mcg and 100/125/25 mcg and in Comparison With FF/VI (100/25 mcg) and UMEC/VI (62.5/25 mcg).
Brief Summary: This study will evaluate the pharmacokinetics of FF, UMEC and VI administered from one inhaler (at two different strengths of UMEC (125 and 62.5microgram \[mcg\]) and FF/VI (ICS/LABA) and UMEC/VI (LAMA/LABA).

Subjects will receive each of the four treatments once, separated by a wash-out period of 7-21 days between doses in a four way crossover design. There will be 4 treatment periods in total. During each treatment period, subjects will attend the clinical unit on Day -1 for standard safety assessments in addition to familiarization with the inhaler. Each subject will remain resident in the unit until at least 24 hours after the dose given on Day 1. Following completion of all four treatment periods, a follow up visit will take place 7 to 21 days following the final dose of study medication.


Options:
A: 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 adequately controlled
* Significant allergy or hypersensitivity to anticholinergics, beta2-agonists, 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 GW642444
B: Inclusion Criteria:

* Healthy male or females at ratio of 1:1, aged 18 - 45 years . Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
* Body weight ≥ 50kg and body mass index (weight/height2) within the range of 19 - 24 kg/m2, inclusive.
* Male or female subjects at the time of signing the informed consent:
* Female subject who is child-bearing potential should agree to use one of the contraception methods (contraceptives intrauterine device, implantable progesterone device or oral contraceptive) for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. The subjects must agree to use contraception until completion of the follow-up visit.
* Male subjects have to agree to use one of the contraception methods listed in Section 8.1.2. This criterion is to be followed from the time of the first dose of study medication until completion of the follow-up visit
* Normal systolic (90-139mmHg) and diastolic (60-89mmHg) blood pressure at pre-study screening.
* Subjects who are current non-smokers, who have not used any tobacco products in the 6 month period preceding the screening visit, and have a pack history of 10 pack years. (pack years = (cigarettes per day smoked/20) × number of years smoked)).
* No significant abnormality on 12-lead ECG at screening, QTcF interval must be \<450msec (QTcF; machine or manual reading).
* AST (SGOT), ALT (SGPT), and total-bilirubin 1.5xULN at screening. No significant clinical abnormality on other laboratory tests.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Subjects who are able to use the inhalation device satisfactorily

Exclusion Criteria:

* As a result of medical interview, physical examination or screening investigations, the principle investigator or delegate physician deems the subject unsuitable for the study.
* History of mental, cardiac, renal, hepatic, significant gastrointestinal or respiratory disease as judged by the investigator
* 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 chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities. A chest X-ray must be taken at day -1 of the first treatment if a chest X-ray or CT scan is not available within 6 months prior to that day.

History of sensitivity to heparin, heparin-induced thrombocytopenia, or sensitivity to any of the study medications, or components thereof, known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and magnesium stearate (MgSt), or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.

* The subject has taken prescription or non-prescription drugs, including CYP3A/PGP inhibitor, 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 Sponsor the medication will not interfere with the study procedures or compromise subject safety.
* Positive result of urine cotinine test.
* The subject has a history of cholecystectomy or biliary tract disease.
* The subject has a significant clinical history or current conditions of glaucoma.
* The subject has a significant clinical history or current conditions of prostatic hypertrophy.
* The subject has a positive pre-study drug screen. A minimum list of drugs that were screened for included amphetamines, barbiturates, cocaine, opiates and benzodiazepines. The detection of drugs with a legitimate medical use was not necessarily an exclusion to study participation. The detection of alcohol was not an exclusion at screening but had to be negative pre-dose and during the study.
* History of regular alcohol consumption within 3 months of the study defined as:
* Abuse of an average weekly intake of greater than 21 units or an average daily intake of greater than three units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than two units (females). One unit was equivalent to a half-pint (220 mL) of beer or one (25 mL) measure of spirits or one glass (125 mL) of wine.
* Female subjects, who are pregnant, planned pregnancy or lactation.
* 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).
* Blood donation or sampled as a study subject within three months preceding the first dose of study drug and blood donation during the entire study in excess of 500mL.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* The subject has tested positive for HIV antibodies.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Subject is mentally or legally incapacitated.
C: Inclusion Criteria:

Safety

* Average Corrected QT Interval using Fridericia's formula (QTcF) \<450 msec at screening.
* Forced Expiratory Volume in 1 second (FEV1) \>=80% predicted and a FEV1/Forced Vital Capacity (FVC) ratio \>=0.7 at screening.
* Alanine transaminase (ALT), alkaline phosphatase and bilirubin \<=1.5x Upper Limit Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

Population

* Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and lung function testing. 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 GSK medical monitor consider the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures and outcome.
* Subjects who are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit and have a pack history of \<=10 pack years. \[number of pack years = (number of cigarettes per day /20) x number of years smoked\]
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* A female subject is eligible to participate as follows: Non-childbearing potential, females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods and women of childbearing potential should have used one of the contraception methods.
* Body Mass Index (BMI) within the range 18.0-33.0 kg/m2 (inclusive).

Exclusion Criteria:

Safety

* Lactating or pregnant females as determined by positive serum or urine hCG test at screening or Day -1.
* A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.

Hepatic Disease

* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or a history of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Concurrent Disease

* History of respiratory disease (i.e. history of asthmatic symptoms) in the last 10 years.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or a positive test for HIV.

Concurrent Medication

* Unable to refrain from the 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.

Population

* A positive pre-study drug/alcohol screen at screening and Day -1.
* 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), or has had exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* 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.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Subject is mentally or legally incapacitated.
* The subject is unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and pummelos, exotic citrus fruits, grapefruit hybrids or any fruit juices containing these fruits from 7 days prior to the first dose of study medication and for the duration of the study.
D: Inclusion Criteria:

* Healthy.
* Male or female 18 to 65 years of age inclusive.
* Non-childbearing women or women of child bearing potential who agree to use contraception
* Subject has had their CYP2D6 genotype confirmed and can be included in either of the following parts:
* Part 1: may include extensive, intermediate and ultra-rapid metabolizers
* Part 2: includes only poor (no enzyme activity) metabolizers, with previously confirmed phenotype
* Body Mass Index within the range 18 - 30 kg/m2 (inclusive).
* Capable of giving written informed consent
* Normal ECG;
* Normal lung function.
* 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
* 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). 24hr Holter monitoring outside normal limits.
* A history of breathing problems (i.e. history of asthmatic symptomatology).
* Abnormal ECG.
* Abnormal blood pressure.
* Abnormal heart rate
* The subject has a positive pre-study drug/alcohol screen.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within three months of screening.
* A positive test for HIV antibody (if determined by the local SOPs).
* History of high alcohol consumption within three months of the study
* The subject has participated in a clinical trial and has received an IP within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the IP (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, (except for simple analgesics e.g. paracetamol), including vitamins, herbal and dietary supplements (including St John's Wort) within seven days (or 14 days if the drug is a potential enzyme inducer) or five half-lives (whichever is longer) prior to the first dose of study medication
* 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 500mL within a 56 day period.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* 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 milk protein or the excipients magnesium stearate and lactose monohydrate.

Answer: C