Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) to Reduce Oral Corticosteroid Use in Patients With Uncontrolled Asthma on High Dose Inhaled Corticosteroid Plus Long-acting β2 Agonist and Chronic Oral Corticosteroid Therapy (ZONDA)
Brief Summary: The purpose of this trial is to confirm if benralizumab can reduce the use of maintenance OCS in systemic corticosteroid dependent patients with severe refractory asthma with elevated eosinophils.


Options:
A: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. Female and male aged from 18 to 75 years, inclusively.
3. History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA.
4. Elevated level of peripheral blood eosinophil
5. Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1
6. Chronic oral corticosteroid therapy for at least 6 continuous months directly preceding Visit 1. Subjects must be on doses equivalent to 7.5 - 40 mg/day of prednisolone/prednisone at Visit 1 and be on a stable dose for at least 2 weeks prior to randomization. Patients must agree to switch to study required prednisone/prednisolone as their oral corticosteroid for the duration of the study.
7. Patients with documented failures of OCS reduction within 6 months prior to Visit 1 will not be required to proceed through the dose optimization phase during run-in.
8. Morning pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted
9. Evidence of asthma as documented by either:

   Airway reversibility (FEV1 ≥12% and 200 mL) demonstrated at Visit 1, Visit 2, or Visit 3 using the Maximum Post-bronchodilator Procedure OR Documented reversibility in the previous 24 months prior to Visit 1 OR Airway hyperresponsiveness (PC20 FEV1 methacholine concentration ≤8mg/mL) documented in the previous 12 months prior to planned date of randomization OR Airflow variability in clinic FEV1 ≥20% between 2 consecutive clinic visits documented in the 12 months prior to the planned date of randomization (FEV1 recorded during an exacerbation should not be considered for this criterion).

   All patients must have reversibility testing performed before randomization to establish a baseline characteristic.

   If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomization, the site should reiterate the need to withhold short- and long-acting bronchodilators prior to Visit 3 in an effort to meet this inclusion criterion.
10. At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained
11. Optimized OCS dose reached at least 2 weeks prior to randomization
12. Additional asthma controller medication must not have been initiated during run in/optimization period (not applicable for management of exacerbations during screening/ run in optimization phase)
13. At least 70% compliance with OCS use
14. At least 70% compliance with usual asthma controller ICS-LABA
15. Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary)

Exclusion criteria:

1. Clinically important pulmonary disease other than asthma or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 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, hematology, clinical chemistry, or urinalysis during run-in/optimization 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
5. History of life-threatening asthma
6. Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase
7. Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5
8. Receipt of oral corticosteroids, other than prednisone or prednisolone, as the maintenance oral steroid controller for asthma symptoms from Visit 1 and throughout the study.
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period
B: Inclusion Criteria:

* Males or infertile females
* Subjects with asthma, well controlled on inhaled corticosteroid and taken as required (PRN) short acting beta 2 agonist therapy only
* Unchanged dose of inhaled corticosteroid for 3 months prior to Day 0 and no expected need for change in dose during study
* Forced expiratory volume in 1 second (FEV1) greater than or equal to 80% predicted at Screening (Baseline)
* 18-60 years
* General Practitioner diagnosis of asthma of 1 year's minimum duration (with respect to Day 0)
* No significant abnormality on clinical examination or medical history (excluding atopic skin signs, symptoms and history)
* 12-lead electrocardiogram with no clinical significant abnormality
* Clinical chemistry hematology and urinalysis results within the laboratory reference ranges or deemed not clinically significant by the Investigator
* A negative screen for drugs of abuse and alcohol
* Body weight between 50-120 kg
* Subjects aged between 18-40 years inclusive must have body mass index (BMI) 18-32 kilogram per square meter (kg/m\^2) inclusive. Subjects aged between 41-60 years must have BMI between 18-30 kg/m\^2 inclusive.

Exclusion Criteria:

* Active concomitant disease, with exception of eczema
* Expected onset of seasonal allergy before the administration of the last dose of study medication
* History of severe exacerbation within 3 years of Day 0
* Recorded use of inhaled short acting beta 2 agonist medication for symptoms within 14 days of Day 0 of: More than 6 doses per day on any 1 day or more than 3 doses per day on 6 or more days
* Any medication other than: inhaled short-acting beta 2 agonist, inhaled corticosteroids, topic eczema treatments (with the exception of fluorinated corticosteroid, dermatological preparations which are not permitted), hormone replacement therapy, vitamin preparation/food supplements, occasional use of proton pump inhibitors, ranitidine, cimetidine, antacids or over-the-counter analgesics
* Treatment within 6 months of Day 0 with any of the following: methylxanthines, inhaled cromones, leukotriene modifiers, anti- immunoglobulin E (IgE), anticholinergics, ketotifen, oral short acting B2 agonists, long-acting B2 agonists, oral or injected corticosteroids
* Treatment of atopic symptoms, other than eczema, within 4 weeks of Day 0
* History of medication that might carry-over effects into the study
* Previously received monoclonal antibody, or a similar related protein, that might sensitize to CAT-354
* Participation in another study within three months of the start of the study or 5 half lives of the previously administered investigational medicinal product (IMP), whichever is longer
* Lower respiratory tract infection within 4 weeks of Day-14
* Any acute illness in the two weeks before Day 0
* Current smokers, those who have smoked in previous year, and those with smoking history of greater than or equal to 10 pack years
* Considered by the investigator to be at risk of transmitting, through blood, the agents responsible for infectious diseases
* Blood donation (550 ml) in the previous 2 months
* Excessive intake of alcohol (more than 21 units a week for females or 28 units a week for males)
* The subject's general practitioner has suggested a reason the subject should not participate in the study
* The Investigator considers the subject should not take part for any reason.
C: Inclusion Criteria:

* The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma.
* The patient has had at least 1 asthma exacerbation requiring oral, intramuscular (im), or intravenous (iv) corticosteroid use for at least 3 days over the past 12 months before screening.
* The patient has a current blood eosinophil level of at least 400/μl.
* The patient has airway reversibility of at least 12% to beta-agonist administration.
* The patient has an ACQ score of at least 1.5 at the screening and baseline (before the 1st dose of study drug) visits.
* The patient is taking inhaled fluticasone at a dosage of at least 440 μg, or equivalent, daily. Chronic oral corticosteroid use (no more than 10 mg/day prednisone or equivalent) is allowed. If a patient is on a stable dose, eg, 2 weeks or more of oral corticosteroid treatment at the time of study enrollment, the patient must remain on this dose throughout the study. The patient's baseline asthma therapy regimen (including but not limited to inhaled corticosteroids, oral corticosteroids up to a maximum of 10 mg of prednisone daily or equivalent, leukotriene antagonists, 5-lipooxygenase inhibitors, or cromolyn) must be stable for 30 days prior to screening and baseline, and must continue without dosage changes throughout study.
* All female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test ß-human chorionic gonadotropin \[ß-HCG\]) at screening (serum) and baseline (urine).
* Female patients of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study.
* Written informed consent is obtained. Patients 12 through 17 years old must provide assent.
* The patient is in reasonable health (except for diagnosis of asthma) as judged by the investigator, and as determined by a medical history, medical examination, ECG evaluation (at screening), serum chemistry, hematology, and urinalysis.

  * Other criteria apply; please contact the investigator for more information.

Exclusion Criteria:

* The patient has a clinically meaningful co-morbidity that would interfere with the study schedule or procedures, or compromise the patient's safety.
* The patient has known hypereosinophilic syndrome.
* The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis) will also be excluded.
* The patient is a current smoker (ie, has smoked within the last 6 months prior to screening).
* The patient is using systemic immunosuppressive or immunomodulating or other biologic agents (including, but not limited to, anti-IgE mAb, methotrexate, cyclosporin, interferon-α, or anti-tumor necrosis factor \[anti TNF\] mAb) within 6 months prior to screening.
* The patient has previously received an anti-hIL-5 monoclonal antibody (eg, reslizumab, mepolizumab, or benralizumab).
* The patient has any aggravating medical factors that are inadequately controlled (eg, rhinitis, gastroesophageal reflux disease, and uncontrolled diabetes).
* The patient has participated in any investigative drug or device study within 30 days prior to screening.
* The patient has participated in any investigative biologics study within 6 months prior to screening.
* Female patients who are pregnant, nursing, or, if of childbearing potential, and not using a medically accepted, effective method of birth control (eg, barrier method with spermicide, abstinence, IUD, or steroidal contraceptive \[oral, transdermal, implanted, and injected\]) are excluded from this study. NOTE: Partner sterility alone is not considered an acceptable form of birth control.

  * Other criteria apply; please contact the investigator for more information.
D: 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

Answer: A