Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Repeat-dose, Placebo-controlled, Double-blind Study to Evaluate and Compare the Efficacy of Fluticasone Furoate/Vilanterol Inhalation Powder, When Administered Either in the Morning or in the Evening, in Male and Female Asthmatic Subjects
Brief Summary: This study will be a repeat-dose, double-blind, randomized, placebo controlled, three-way crossover study in patients with persistent bronchial asthma to compare the effect of morning (AM) and evening (PM) dosing with fluticasone furoate (FF)/Vilanterol (VI) inhalation powder on lung function. Following screening there will be a run-in period of 14 days. There will be 3 treatment periods; drug at AM, drug at PM and placebo, which will last for 14 days each with a 14-21 day washout period between starting the next. Key assessments include; forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), vital signs, electrocardiograms (ECGs), adverse event (AE) monitoring and laboratory safety tests.


Options:
A: Inclusion Criteria:

* Subjects with a documented history of persistent asthma, with the exclusion of other significant pulmonary diseases.
* Male or female between 18 and 70 years of age inclusive
* A female subject is eligible to participate if she is of:

  * 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 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment.
  * Child-bearing potential and agrees to use one of the protocol contraception methods.
* All subjects must be using an inhaled corticosteroid (ICS), with or without a short-acting, beta2-receptor agonist (SABA), for at least 12 weeks prior to screening.
* Subjects with a screening pre-bronchodilator FEV1 ≥ 60% of predicted.
* During the screening visit, subjects must demonstrate the presence of reversible airway disease.
* All subjects must be able to replace all their current asthma treatments with albuterol/salbutamol aerosol inhaler at screening for use as needed for the run-in period and throughout the duration of the study. Subjects must be able to withhold albuterol/salbutamol for at least 6 hours prior to study visits.
* Subjects who are current non-smokers, who have not used any inhaled tobacco products in the 12 month period preceding the screening visit.
* Body weight ≥ 50 kg and Body Mass Index (BMI) within the range 19.0-29.9 kg/m2 (inclusive).
* No evidence of significant abnormality in the 12-lead ECG performed at screening.
* Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \< 2x Upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Capable of giving written informed consent
* Able to satisfactorily use the novel dry powder inhaler.

Exclusion Criteria:

* A history of life-threatening asthma within the last 5 years.
* Culture-documented or suspected bacterial or viral infection that is not resolved within 4 weeks of screening and led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
* Any asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to screening.
* A subject has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation.
* A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening.
* Pregnant females.
* Lactating females.
* The subject has participated in a clinical trial and has received an investigational product within 30 days prior to the first dosing day in the current study.
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Any adverse reaction including immediate or delayed hypersensitivity to any beta 2- agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy.
* History of severe milk protein allergy.
* History of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Use of prescription or non-prescription drugs 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.
* Subjects who have taken high doses of an ICS within 8 weeks of the screening visit or oral steroids within 12 weeks of the screening visit.
* Subjects who have changed their ICS treatment within the last 4 weeks before screening or can be expected to do so during the study.
* History of regular alcohol consumption within 6 months of the study.
* A positive test for Hepatitis B or Hepatitis C within 3 months of screening.
* A positive breath carbon monoxide (CO) test.
* A positive pre-study drug/alcohol screen.
* A positive test for Human Immunodeficiency Virus (HIV) antibody.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* No subject is permitted to perform night shift work for 1 week prior to screening until completion of the study treatment periods.
* Unwillingness or inability to follow the procedures outlined in the protocol.
B: Inclusion criteria:

* healthy males and females (of non-childbearing potential) aged 18-55
* body weight \>50kg with BMI 19-29.9 kg/m2
* normal ECG recording
* non-smoker

Exclusion criteria:

* high blood pressure (above 140/90 mmHg)
* pulse outside range 45 - 90 bpm
* history of breathing problems e.g. asthma
* low haemoglobin (\<11 g/dL)
* blood donation within 56 days of study start
* taking regular medication
* participation in another trial within 4 months of study start
* history of drug or alcohol abuse
* abnormal clinical laboratory tests
* known allergies
C: Inclusion Criteria:

* Body mass index within the range 18.5-35.0 kilograms/metre2 (kg/m2).
* Females of non-child bearing potential.
* Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit and currently being treated only with intermittent short-acting beta -agonist therapy by inhalation
* Pre-bronchodilator FEV1 \>70% of predicted at screening
* Subjects who are current non-smokers
* Methacholine challenge PC20 \< 8 mg/mL at screening
* Screening allergen challenge demonstrates that the subject experiences an early asthmatic response

Exclusion Criteria:

* Current or chronic history of liver disease, or known hepatic or biliary abnormalities
* Subject is hypertensive at screening
* Respiratory tract infection and/or exacerbation of asthma within 4 weeks prior to the first dose of study medication.
* History of life-threatening asthma
* Symptomatic with hay fever at screening or predicted to have symptomatic hayfever
* Unable to abstain from short acting beta agonists
* Unable to abstain from antihistamines
* Unable to abstain from other medications including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-asthma anti-rhinitis or hay fever medication
* The subject has participated in a study with a new molecular entity during the previous 3 months or has participated in 4 or more clinical studies in the previous 12 months
* undergoing allergen desensitisation therapy
D: Inclusion Criteria:

* Subjects with a documented history of persistent asthma, with the exclusion of other significant pulmonary diseases (e.g. chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis or bronchopulmonary dysplasia).
* Male subjects or female subjects aged between 18 to 70 years.
* 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.
  * Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 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. Female subjects must agree to use contraception until 2 days post last-dose.
* Subjects who are current non-smokers, who have not used any inhaled tobacco products (snuff is permitted) in the 12 month period preceding the screening visit and who have a pack history of ≤ 10 pack years.
* Subjects with clinically stable, mild to moderate persistent asthma within the 4 weeks preceding the screening visit and with a screening pre-bronchodilator FEV1 ≥ 60 % predicted as defined in the GINA guidelines \[Global Initiative for Asthma (GINA), 2006\] (having abstained from bronchodilators for the required period). Predicted values are based on the ECCS 1993 normal ranges.
* Body weight ≥ 50 kg and body mass index (BMI) within the range 19 - 29.9 kg/m2
* During the screening visit, subjects must demonstrate the presence of reversible airway disease, defined as an increase in FEV1 of ≥ 12.0% over baseline and an absolute change of ≥ 200 mL within 30 minutes following a single 400 mcg salbutamol dose.
* ECG criteria as per protocol
* Subjects who are currently taking ICS at a total daily dose of 200 to 500 mcg of FP or equivalent ICS.
* Subjects who are able and willing to give written informed consent to take part in the study.

Exclusion Criteria:

* Subjects who have a past or present disease, which as judged by the Investigator and the Medical Monitor, which may affect the safety of the subject or outcome of this study.
* A screening Holter ECG tracing that reveals clinically concerning arrhythmias.
* Subjects who have suffered an upper or lower respiratory tract infection within 4 weeks of the screening visit
* Subjects with a history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with either respiratory arrest or hypoxic seizures.
* Asthma exacerbations requiring treatment with oral corticosteroids: any exacerbations within 3 months of the screening visit or two or more exacerbations within 6 months of the screening visit or admittance to hospital for an asthma exacerbation within 1 year of the screening visit.
* Subjects classified as suffering from severe asthma as defined by the ATS guidelines
* Subjects who have taken high doses of an inhaled corticosteroid (\> 500 mcg FP/day or equivalent) within 8 weeks of the screening visit or oral steroids within 12 weeks of the screening visit.
* Subjects who have changed their inhaled corticosteroid treatment within the last 6 weeks before screening or can be expected to do so during the study.
* 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 NCE's within 12 months prior to the first dosing day
* Any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug, or known or suspected sensitivity to the constituents of GW642444 inhalation powder (e.g., lactose, milk protein, magnesium stearate).
* Subjects with a positive pre-study Hepatitis B surface antigen, positive Hepatitis C antibody or HIV result (if tested as per site SOPs) within 3 months of the start of the study.
* Neurological or psychiatric disease or history of drug or alcohol abuse which would interfere with the subject's proper completion of the protocol requirements, including compliance.
* Abuse of alcohol is 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).
* 1 unit is equivalent to a half pint (220 mL) of beer or 1 measure (25 mL) of spirits or 1 glass (125 mL) of wine.
* The subject has a positive pre-study urine drug test screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
* The subject has a positive pre-study alcohol or smoking breath or urinary test.
* Where participation in the study would result in donation of blood in excess of 500 mL within a 56 day period.
* Subjects with clinically relevant findings on laboratory safety tests.
* Subjects with laboratory values outside the reference range may be included if the Investigator and medical monitor agree that these findings would not put the subject at risk or interfere with the objectives of the study.
* Subjects with known hypersensitivity to salbutamol or any ingredient in this preparation
* Subjects who have taken P-gp inhibitors and CYP 450 3A4 inhibitors (e.g. Ketoconazole) within 6 weeks or theophyllines within 2 weeks of the screening visit.
* Inability to use the novel dry powder inhaler.
* Pregnant females as determined by positive hCG (serum or urine) test at screening or prior to dosing.
* Lactating females.
* Unwillingness or inability to follow the procedures outlined in the protocol.

Answer: A