Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Single-dose, Double-blind, Placebo-controlled, 5-way Crossover Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Inhaled Doses of GW642444M With and Without Magnesium Stearate in Asthmatic Patients
Brief Summary: This study will involve the use of a new medicine called GW642444 being developed for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The purpose of the study is to see how safe and how well tolerated the study drug is when inhaled in two different formulations as a fine powder by asthmatic patients. In addition, the study is designed to examine the effect of the study drug on the lungs, how the study drug affects parts of the body other than the lungs and to see how the body affects the study drug when it is given in single doses.


Options:
A: Inclusion Criteria:

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

1. Informed consent: Subjects must be able to provide informed consent, have their consent signed and dated.
2. Type of subject: Subjects with documented GP diagnosis of asthma as their primary respiratory disease.
3. Current Anti-Asthma Therapy: All subjects must be prescribed maintenance therapy and receiving ICS with or without LABA (either a fixed combination or via separate inhalers), and for at least 4 weeks prior to Visit 2.

   * Other background asthma medication such as anti-leukotrienes are permitted
4. All subjects on ICS monotherapy or ICS/LABA combination (this can be a fixed dose combination or an ICS alone or LABA alone in separate inhalers) must have had symptoms in the past week prior to Visit 2. Symptoms are defined by daytime symptoms more than twice per week, use of short-acting beta2-agonist bronchodilator more than twice per week, any limitation of activities, or any nocturnal symptoms/awakening. (The symptoms are based on subject's recall and are consistent with the GINA and in principal with the BTS/SIGN guidelines).
5. Subject questionnaires: Subjects must be able to complete the electronic subject questionnaires as well as those questionnaires that are completed by phone or provide a proxy e.g. a partner/relative/a friend who can do so on their behalf
6. Gender and Age: Male or female subjects aged ≥18 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 (\<147 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).

Exclusion Criteria:

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

1. Recent history of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 6 months.
2. COPD Respiratory Disease: A subject must not have current evidence or GP diagnosis of chronic obstructive pulmonary disease.
3. 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.
4. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g., beta2-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.
5. Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 2 or within five half-lives (t½) of the prior investigational study (whichever is longer of the two), (if unsure discuss with the medical monitor prior to screening)
6. Chronic user of systemic corticosteroids: A subject who, in the opinion of the GP/Investigator, is considered to be a chronic user of systemic corticosteroids for respiratory or other indications (if unsure discuss with the medical monitor prior to screening)
7. Subjects who are using LABA without an ICS as asthma maintenance therapy.
8. 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.
B: Inclusion Criteria:

* Clinical diagnosis of asthma
* Reversibility of at least 12% and at least 200mLs within 10-40 minutes following 2-4 inhalations of albuterol
* FEV1 of 40-85% predicted normal
* Currently using inhaled corticosteroid therapy

Exclusion Criteria:

* History of life-threatening asthma within previous 5 years (requiring intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxic seizures)
* Respiratory infection or oral candidiasis
* Asthma exacerbation requiring oral corticosteroids or that resulted in overnight hospitalisation requiring additional asthma treatment
* Uncontrolled disease or clinical abnormality
* Allergies
* Taking another investigational medication or prohibited medication
* Night shift workers
* Current smokers or subjects with smoking history of at least 10 pack years
C: 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.
D: Inclusion criteria:

* Male or female (of non-childbearing potential) \> or = 40 years
* History of COPD
* Smoker or ex-smoker
* Body weight \> or = 50 kg with BMI 18-32 kg/m2

Exclusion criteria:

* History of significant disease
* Subjects with a primary asthma diagnosis
* Alpha-1 antitrypsin deficiency as underlying cause of COPD
* Recent respiratory tract infection
* Poorly controlled COPD
* Blood potassium level \< 3.5mmol/L
* Short-term or long tern oxygen therapy
* Recent participation in another trial
* History of drug or alcohol abuse
* Known allergies
* Recent blood donation
* ECG abnormalities

Answer: C