Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose Ranging Study to Determine the Effect of Mepolizumab on Exacerbation Rates in Subjects With Severe Uncontrolled Refractory Asthma
Brief Summary: The purpose of this study is to show whether mepolizumab given every 4 weeks intravenously (i.v.) can reduce the frequency of asthma exacerbations in subjects with severe asthma despite receiving high doses of standard asthma medications. The study will look at different doses of mepolizumab in comparison to a placebo.


Options:
A: Inclusion Criteria:

Patients who met the following criteria were included:

* Males or females of any race, who were 12-75 years of age
* A body weight ≥ 20 kg and ≤ 150 kg and with a total serum IgE level ≥ 30 to ≤ 700 IU/ml
* A diagnosis of allergic asthma ≥ 1 year duration according to American Thoracic Society (ATS) criteria and at screening a history consistent with GINA (2204) step 3 or 4 clinical features
* A positive prick skin test (diameter of wheal \>= 3 mm) to at least one perennial allergen documented within the past 2 years or taken at visit 1
* Increase in FEV1 ≥12% over baseline value within 30 minutes of taking 2 to 4 puffs (2-4x100µg) salbutamol (albuterol) or nebulized salbutamol up to 5mg
* An FEV1 ≥ 40 and ≤ 80% of the predicted normal value for the patient at randomization
* Receiving moderate to high dose inhaled corticosteroid ≥ 800 µg BDP or equivalent and a regular inhaled long acting B-2 agonists for at least 3 months prior to screening and \> 1000 µg (BDP) and a LABA for at least 4 weeks during the run-in and at randomization
* Patients who have suffered multiple (i.e. at least two) independent documented severe asthma exacerbations while receiving high doses of ICS (≥ 800 µg BDP or equivalent) plus regular inhaled LABA
* Evidence of poor asthma control at screening (based on patient history) and for at least 4 weeks immediately prior to randomisation

Exclusion Criteria:

Patients who met the following criteria were excluded:

* Had received systemic corticosteroids for reasons other than asthma within 4 weeks of Visit 1
* A smoking history \>10 pack years
* An active lung disease other than allergic asthma
* Elevated serum IgE levels for reasons other than allergy
* Patients with significant underlying medical conditions
B: Inclusion Criteria:

* Male or female
* Aged 12 to 65 years inclusive
* Minimum weight 45kg
* Clinical features of severe refractory asthma
* Well documented requirement for high dose inhaled corticosteroids (ICS) \[i.e. \>= 880mcg/day fluticasone propionate or equivalent daily\] for at least 12 months
* Using additional controller medication in addition to high dose ICS for at least 12 months
* Persistent airflow obstruction indicated by a pre-bronchodilator FEV1\<80% predicted at visit 1 or 2 or peak flow diurnal variability of \>20% on 3 or more days during the run-in
* Airway inflammation which is likely to be eosinophilic in nature demonstrated by either raised peripheral blood eosinophils (\>=300/microL), sputum eosinophils (\>=3%), exhaled nitric oxide (\>=50ppb) or prompt deterioration of asthma control following a \<=25% reduction in regular maintenance dose of inhaled or oral corticosteroids (OCS)
* History of 2 or more exacerbations requiring systemic corticosteroids in the previous 12 months
* Evidence of asthma documented by airway reversibility, airway hyperresponsiveness or airflow variability
* ECG assessment demonstrating QTc\<450msec or QTc\<480msec for patients with bundle branch block
* Liver function tests demonstrating ALT\<2xUpper Limit of Normal (ULN), AST\<2xULN, Alk Phos \<=1.5xULN, bilirubin \<=1.5xULN
* Female of non-child-bearing potential or child-bearing potential with a negative pregnancy test at screening and prepared to agree to an acceptable method of contraception
* Able to give written informed consent
* Able to read, comprehend and write at a sufficient level to complete study materials

Exclusion Criteria:

* Current smokers or smoking history of \>=10 pack years
* Clinically important lung condition other than asthma
* Diagnosis of malignancy or in the process of investigation
* Unstable liver disease
* Churg-Strauss syndrome
* Using methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine or any experimental anti-inflammatory therapy within 3 months of screening
* Omalizumab (Xolair) or any other biological for the treatment of inflammatory disease within 6 months of Visit 1
* Regular use of oral or systemic corticosteroids for diseases other than asthma within 12 months or any intra-articular, short-acting intramuscular corticosteroid within 1 month or intramuscular, long-acting depot corticosteroid within 3 months
* Allergy/intolerance to the excipients in the mepolizumab formulation
* Any investigational drug within 30 days or 5 terminal half-lives, whichever is longer
* Pregnant or breastfeeding or planning to become pregnant
* Clinically significant disease which is uncontrolled with standard treatment
* History of alcohol misuse or substance abuse
* Parasitic infestation within previous 6 months
* Known immunodeficiency
* Unable to follow instructions, use the electronic diary or peak flow meter
* Known evidence of lack of adherence to controller medications and/or follow physician's recommendations
* Previous participation in a study of mepolizumab and received study medication within 90 days
C: Inclusion criteria:

* Men aged 18 - 65 years inclusive, or women aged 18 - 50 years inclusive.
* Female subjects must be of non-childbearing potential,
* Male subjects must agree to abstain from sexual intercourse or use adequate contraception during sexual intercourse with pregnant or lactating females, in addition to their female partner using another form of contraception. This criterion must be followed from the time of the first dose of study medication until 84 days after the last dose of study medication.
* Body weight ≥ 50 kg and BMI within the range 19 - 29.9 kg/m2.
* Non-smoker as verified by urinary cotinine levels below 300 ng/mL at screening or ex-smokers who have given up smoking for \>12 months with a history \<10 pack years \[Pack yrs = (No of cigarettes/day x No of years smoked)/20\]
* Available to complete all study measurements.
* Able to read, comprehend, and write English at a sufficient level to complete study related materials.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Additional Inclusion Criteria for Subjects in Part I

• Healthy as determined by a responsible physician, based on a medical evaluation including history, physical examination, laboratory tests, cardiac monitoring.

Additional Inclusion Criteria for Subjects in Part II

* History of asthma for at least 6 months prior to the screening visit currently requiring no treatment or intermittent treatment with inhaled short-acting beta2-agonist only. Subject must not have received low dose inhaled corticosteroids within three months prior to Day 0.
* Pre-bronchodilator FEV1 \>70% but \<90% of predicted at screening with ≥12% reversibility after short-acting beta2-agonist or If the subject has a pre-bronchodilator FEV1 ≥90% at screening but has a history of asthma or if the subject meets the FEV1 criteria but does not demonstrate ≥12% reversibility after short-acting beta2-agonist administration, then the subject may be considered eligible if a Bronchial Provocation Test for asthma is positive (and after consultation with Medical Monitor and Principal Investigator). The bronchial provocation will be considered positive when the standard criteria for a positive response with the given challenge agent are met.
* Skin prick test positive for an allergen that is appropriate for nasal challenge

Exclusion criteria:

* As a result of medical interview, physical examination or screening investigations, the responsible physician deemed the subject unsuitable for the study.
* 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 physician responsible, contraindicates their participation.
* Previous exposure to humanised antibody therapy for any reason.
* A strong family history of Th1 cytokine-related inflammatory disorders, including but not limited to, Type I diabetes mellitus, multiple sclerosis, Crohn's disease, rheumatoid arthritis, sarcoidosis.
* Known history of active or latent tuberculosis, or recent (within 6 months of study enrolment) exposure to a person with active tuberculosis. Previous medical history and letter from the subject's physician (GP) should exclude this.
* A history of chronic urogenital infections or other chronic infections.
* Subjects who have received any type of vaccination in the last two months.
* The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug(whichever is longer) prior to the first dose of current study medication
* Where participation in study would result in donation of blood in excess of 500 mL within a 56 day period
* 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'sWort) 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.
* History of alcohol/drug abuse or dependence within 12 months of the study:
* Abuse of alcohol 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 (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* A positive test for human immunodeficiency virus (HIV) antibodies.
* The subject has a positive pre-study urine drug/ urine alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
* ECG that is outside of ranges as defined by the protocol
* Those who, in the opinion of the Investigator, have a risk of non-compliance with study procedures.
* The subject has a history of confirmed or active parasitic infection.
* The subject is unable to refrain from travelling to countries with a high prevalence of infectious (especially parasitic) disease from when the first dose is administered until the expected washout period is complete (plasma levels below LLQ) or the last follow-up visit, which ever is later
D: Inclusion criteria:

* Parent or legal guardian was informed of the study procedures and medications and gave written informed consent.
* Outpatient males and females aged 6 - \< 12 years on study entry, with body weight between 20 and 150 kg.
* Total serum IgE level ≥ 30 to ≤ 1300 IU.
* Diagnosis of allergic asthma ≥ 1 year duration, according to American Thoracic Society (ATS) criteria, and a screening history consistent with clinical features of moderate or severe persistent asthma according to National Heart Lung and Blood Institute (NHLBI) guidelines.
* Positive prick skin test to at least one perennial allergen, documented within the past 2 years or taken at Screening. A radioallergosorbent test (RAST) could have been performed for patients with a borderline skin prick test result after consultation with Novartis clinical personnel.
* Patients with ≥ 12% increase in forced expiratory volume in 1 second (FEV1) over starting value within 30 minutes of taking up to 4 puffs (4x100 µg) salbutamol (albuterol) or nebulized salbutamol up to 5 mg (or equivalent of alternative B2-agonist) documented within the past year, at screening, during the run-in period, or prior to randomization. Patients were not to take their long acting B2-agonist (LABA) medication within 12 hours of reversibility testing.
* Clinical features of moderate or severe persistent asthma (at least step 3) despite therapy at step 3 or 4 (at least medium dose inhaled corticosteroid (ICS) - fluticasone dry-powder inhaler (DPI) ≥ 200 mg/day or equivalent with or without other controller medications).
* Documented history of experiencing asthma exacerbations and demonstrated inadequate symptom control during the last 4 weeks of run-in despite receiving an equivalent dose of fluticasone DPI ≥ 200 mg/day total daily ex-valve dose.

Exclusion criteria:

* Patients who received systemic corticosteroids for reasons other than asthma, beta-adrenergic antagonists by any route, anticholinergics within 24 hours of Screening, methotrexate, gold salts, cyclosporin or troleandomycin, or had received desensitization therapy with less than 3 months of stable maintenance doses prior to Screening.
* Patients with a history of food or drug related severe anaphylactoid or anaphylactic reaction, a history of allergy to antibiotics, with aspirin or other non-steroidal anti-inflammatory drugs (NSAID)-related asthma (unless the NSAID could be avoided), with active lung disease or acute sinusitis/chest infection, elevated serum IgE levels for other reasons, presence/history of a clinically significant uncontrolled systemic disease, cancer, abnormal, electrocardiogram (ECG) in the previous month, or platelets ≤ 100 x 109/L or clinically significant laboratory abnormalities at Screening.

Answer: B