Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicentre, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase III Efficacy and Safety Study of Benralizumab (MEDI-563) Added to High-dose Inhaled Corticosteroid Plus Long-acting β2 Agonist in Patients With Uncontrolled Asthma
Brief Summary: The purpose of this study is to determine whether Benralizumab reduces the number of asthma exacerbations in patients who remain uncontrolled on high doses of ICS-LABA.


Options:
A: Inclusion Criteria:

* History of asthma for 6 or more months
* History of chronic persistent asthma requiring daily high dose inhaled corticosteroid for 3 or more months prior to enrollment

Exclusion Criteria:

* Patients with 10 or more pack years of smoking history or smoking within 12 months of study enrollment
* No significant disease other than asthma
B: 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
C: Inclusion Criteria:

1. Written informed consent for study participation must be obtained prior to any study related procedures being performed (local regulations are to be followed in determining the assent/consent requirements for children and parent\[s\]/guardian\[s\]) and according to international guidelines and/or applicable European Union guidelines.
2. Female and Male aged 12 to 75 years inclusively, at the time of visit 1. For those patients, who are 17 on the day of Visit 1 but will turn 18 after this day, will be considered an adolescent for the purposes of this trial.
3. History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (\>250μg fluticasone dry powder formulation equivalents total daily dose) and a LABA, for at least 12 months prior to Visit 1
4. Documented treatment with ICS and LABA for at least 3 months prior to Visit 1 with or without oral corticosteroids and additional asthma controllers.

   * For subjects 18 years of age and older, the ICS dose must be \>500 mcg/day fluticasone propionate dry powder formulation or equivalent daily.
   * For subjects ages 12-17, the ICS dose must be ≥500 mcg /day fluticasone propionate dry powder formulation or equivalent daily.

Exclusion criteria:

1. Clinically important pulmonary disease other than asthma (e.g. active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, Churg- Strauss syndrome, hypereosinophilic syndrome)
2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

   * Affect the safety of the patient throughout the study
   * Influence the findings of the studies or their interpretations
   * Impede the patient's ability to complete the entire duration of study
3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period
4. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study
D: Inclusion Criteria:

* Physician diagnosis of asthma for greater than or equal to 3 years and a diagnosis of severe persistent asthma forgreater than or equal to 1 year prior to screening
* Continuous treatment with high dose Inhaled corticosteroids (ICS) and long acting beta-agonist for at least 3 months prior to screening
* Have evidence of at least 1 of the following in the 5 years prior to screening or during screening, reversible airway obstruction greater than or equal to 12 percentage change in forced expiratory volume in 1 second (FEV1) postbronchodilator; Diurnal variation in peak expiratory flow rate (PEFR) greater than or equal to 30 percentage change) and airway hyperresponsiveness
* Estimated frequency of symptoms on more than one-third of days for at least 3 months prior to screening (eg, wheezing, breathlessness, chest tightness, cough, nocturnal awakening) despite treatment with high dose ICS and long-acting β2-agonist (LABA), with or without continuous oral corticosteroids
* Score of greater than or equal to 2 points on the asthma control questionnaire at screening.

Exclusion Criteria:

* Diagnosis of chronic obstructive pulmoanry disease (COPD), cystic fibrosis, or other significant respiratory disorder
* Worsening of asthma symptoms that required treatment with an addition or increase in oral corticosteroids dose (steroid burst) in the 4-week period prior to the screening visit
* Life-threatening asthma attack requiring cardiopulmonary support (eg, intubation) in the 6-month period prior to screening
* Have ever used alkylating agents (eg, chlorambucil or cyclophosphamide)
* Concomitant diagnosis or any history of congestive heart failure (CHF), including medically controlled CHF.

Answer: C