Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 12-month, Open Label, Randomised, Effectiveness Study to Evaluate Fluticasone Furoate (FF, GW685698)/Vilanterol (VI, GW642444) Inhalation Powder Delivered Once Daily Via a Novel Dry Powder Inhaler (NDPI) Compared With the Existing COPD Maintenance Therapy Alone in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Brief Summary: This study is designed to compare the effectiveness and safety of Fluticasone Furoate/Vilanterol Inhalation Powder (100mcg Fluticasone Furoate ((FF), GW685698)/25mcg Vilanterol ((VI), GW642444)) delivered once daily via a Novel Dry Powder Inhaler (NDPI) compared with the existing COPD maintenance therapy over twelve months in subjects diagnosed with COPD. This is a Phase III multi-centre, randomised open label study. Subjects who meet the eligibility criteria are randomised and will enter a 12 month treatment period.


Options:
A: 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.
B: Inclusion Criteria:

Subjects eligible for enrolment in the study must meet all of the following criteria:

1. Type of subject: Subjects with documented GP diagnosis of COPD, and currently receiving maintenance therapy
2. Informed consent: Subjects must be able to provide informed consent, have their consent signed and dated. Subjects must be able to complete the electronic subject questionnaires or allow a proxy to do so on their behalf.
3. Gender and Age: Male or female subjects aged ≥40 years of age at Visit 1 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, history of vasomotor symptoms. However in questionable cases, a blood sample with FSH \> 40MIU/ml and estradiol \<40pg/ml (\<140 pmol/L) is confirmatory. Or child bearing potential has a negative urine pregnancy test at Visit 2, and agrees to one of the highly effective and 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 - Visit 2 to the end of the study).
4. Subjects with Exacerbation History
5. Current COPD Maintenance Therapy

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

1. Subjects with any life threatening condition (e.g. low probability (in the opinion of the GP/Investigator) of 12 month survival due to severity of COPD or co-morbid condition) at the point of entry into the study.
2. Other diseases/abnormalities: Subjects with historical or current evidence of uncontrolled or clinically significant disease. Significant is defined as any disease that, in the opinion of the GP/ 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.
3. Subjects with unstable COPD, defined as the occurrence of the following in the 2 weeks prior to Visit 2:

   - Acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician.
4. Chronic user of oral corticosteroids: Subjects who, in the opinion of the GP/Investigator, are considered to be a chronic user of oral corticosteroids for respiratory or other indications (if unsure discuss with the medical monitor prior to screening)
5. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g., beta-agonists, corticosteroid) or components of the inhalation powder (e.g., lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the GP/ Investigator, contraindicates the subject's participation will also be excluded.
6. Investigational Medications: A subject must not have used any investigational drug treatment within 30 days prior to Visit 2 or within five half-lives (t½) of the prior investigational study (whichever is the longer of the two).
7. Subjects who plan to move away from the geographical area where the study is being conducted during the study period and/or if subjects have not consented to their medical records being part of the electronic medical records database that is operational in the Salford area.
C: Inclusion criteria:

* Aged 12 years of age or older at Visit 1 For sites in the following countries, subjects recruited will be ³ 18 years of age: Germany, Hungary and the Russian Federation and any other countries where local regulations or the regulatory status of study medication permit enrolment of adults only.
* Male or eligible 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.

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):

* Complete abstinence from intercourse from screening until 2 weeks after the follow-up contact; or
* Sterilisation of male partner (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for that subject; or
* Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or
* Injectable progestogen administered for at least 1 month prior to study medication administration and administered for 1 month following study completion; or
* Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or
* Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) N.B. For German sites female subjects must use a method of birth control other than the double barrier method
* An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or
* Estrogenic vaginal ring inserted for at least 1 month prior to study medication administration; or
* Percutaneous contraceptive patches in place for at least 1 month prior to study medication administration Female subjects should not be enrolled if they are pregnant, or lactating, or plan to become pregnant during the time of study participation.
* Documented clinical history of persistent asthma, as defined by the National Institutes of Health \[NIH, 2007\] first diagnosed at least 6 months prior to Visit 1.
* Subjects with current reversible airways disease as demonstrated at Visit 1 by an increase in FEV1 of ≥ 12% and ≥ 200ml over the pre-salbutamol/albuterol FEV1 at approximately 30 minutes after the inhalation of 400mcg of salbutamol/albuterol via MDI (spacer permitted for reversibility testing only if required) or one nebulised salbutamol/albuterol solution.
* Subjects must be using an inhaled corticosteroid and have been maintained on a stable dose for 4 weeks prior to Visit 1 at one of the following doses:

Maximum Allowable Concurrent Inhaled Corticosteroid Doses

Asthma Therapy(Maximum Daily Dose (mcg/day)) fluticasone propionate MDI CFC/HFA (≤ 880mcg1/ ≤1000mcg2) fluticasone propionate DPI(≤ 1000mcg) beclomethasone dipropionate(≤ 1680mcg1/ ≤ 2000mcg2) beclomethasone dipropionate HFA (QVAR)(≤ 640mcg1/ ≤ 800mcg2) budesonide DPI/MDI(≤ 2000mcg) Flunisolide(≤ 2000mcg) triamcinolone acetonide(≤ 2000mcg) mometasone furoate(≤ 880mcg) Ciclesonide(≤ 320mcg1/ ≤ 400mcg2)

CFC=chlorofluorocarbon HFA=hydrofluoroalkane

1. Ex-actuator dose
2. Ex-valve dose

   * Pre-bronchodilator FEV1 between ≥ 40 - ≤ 90% predicted at Visit 1. NHANES III predicted values will be used for subjects aged ≥ 12 years and adjustments to predicted values will be made for African American subjects \[Hankinson, 1999\].
   * Appropriately signed and dated informed consent has been obtained.
   * Capable of withholding salbutamol/albuterol use for ≥ 6 hours prior to clinic visits.
   * 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:

* An exacerbation of asthma within 4 weeks of Visit 1, or a culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of Visit 1 that led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study.
* History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia seizures.
* Asthma exacerbation requiring treatment with oral corticosteroids within 3 months prior to Visit 1.
* Hospitalised for an asthma exacerbation within 6 months of Visit 1. Hospitalisation is defined as an overnight stay in a hospital.
* Previously enrolled in this study, or has participated in any study using an investigational drug during the previous 30 days or will participate simultaneously in another clinical trial.
* A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the subject's safety at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study.

The list of additional excluded conditions/diseases includes, but is not limited to the following:

congestive heart failure, known aortic aneurysm clinically significant coronary heart disease, clinically significant cardiac arrhythmia stroke within 3 months of Visit 1, uncontrolled hypertension1 poorly controlled peptic ulcer, haematologic, hepatic, or renal disease immunologic compromise, current malignancy2 tuberculosis (current or untreated3), Cushing's disease Addison's disease, uncontrolled diabetes mellitus uncontrolled thyroid disorder, recent history of drug or alcohol abuse neurological disease, pulmonary disease4

1. systolic blood pressure 160, or diastolic blood pressure \>100
2. history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission = no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
3. Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be enrolled \[American Thoracic Society Documents, 2005\] \[American Thoracic Society (ATS), 2003\]
4. Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.

   * Any adverse reaction including immediate or delayed hypersensitivity to any ß2-agonist or sympathomimetic drug, or known (i.e., patients with a history of severe milk protein allergy) or suspected sensitivity to the constituents of GW642444M inhalation powder (e.g., lactose or magnesium stearate).
   * Subjects who are likely to be non-compliant with study medication and other study-related requirements (e.g. attendance at clinic visits or completion of Daily Diary).
   * Neurological or psychiatric disease or history of drug or alcohol abuse which would interfere with the subject's proper completion of the protocol requirements.

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). The number of units of alcohol in a drink can be determined by multiplying the volume of the drink (in millilitres) by its percentage ABV and dividing by 1000

* Current smoker or a smoking history of 10 pack years or more (e.g. 20 cigarettes/day for 10 years). A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco).
* Administration of systemic, oral or depot corticosteroids or administration of anti-IgE (e.g. omalizumab \[Xolair\]) within 12 weeks of Visit 1.
* Administration of the following asthma medications within 14 days of Visit 1:
* Theophyllines
* Oral β2-agonists (e.g. bambuterol)
* Slow-release bronchodilators
* Anticholinergics - short or long-acting
* Oral long acting antihistamines
* Oral leukotriene receptor antagonists (e.g. montelukast)
D: Inclusion Criteria:

* At least 6 and maximally 15 years of age
* Diagnosis of asthma and baseline lung function tests as determined by the protocol
* Has required and received treatment with inhaled corticosteroids within the timeframe and doses specified in the protocol

Exclusion Criteria:

* Severe asthma
* Has required treatment with any non-inhaled corticosteroids within previous 4 weeks, has sensitivity to drugs specified in the protocol or requires treatment with beta-blockers

Answer: B