Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3b Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients With Severe Asthma Uncontrolled on Standard of Care Treatment
Brief Summary: The purpose of this study is to investigate the effect of benralizumab on the rate of asthma exacerbations, patient reported quality of life and lung function during the 24-week treatment in patients with uncontrolled, severe asthma with an eosinophilic phenotype. A subset of patients will be assessed for their ongoing chronic rhinosinusitis with nasal polyps. The study design has been updated to include a 56-week open label ANDHI in Practice (ANDHI IP) sub study upon the completion of the 24-week double-blind period of the ANDHI study.


Options:
A: Inclusion Criteria:

* The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma. Patients 12 through 17 years of age are excluded from participating in Argentina.
* The patient has an ACQ score of at least 1.5.
* The patient has airway reversibility of at least 12% to beta-agonist administration at screening.
* The patient is currently taking fluticasone at a dosage of at least 440 μg daily (or equivalent). Patients' baseline asthma therapy regimens (including but not limited to inhaled corticosteroids, leukotriene antagonists, 5-lipoxygenase inhibitors, cromolyn) must be stable for 30 days before screening, and continue without dosage changes throughout study.
* The patient has a blood eosinophil count of at least 400/μL.
* Female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test ßHCG 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 the end-of-treatment visit. Acceptable methods of contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected).
* Written informed consent is obtained. Patients 12 through 17 years old, where participating, need to provide assent in accordance with local standards.
* Other inclusion criteria apply.

Exclusion Criteria:

* The patient has a clinically meaningful comorbidity that would interfere with the study schedule or procedures, or compromise the patient's safety.
* The patient has known hypereosinophilic syndrome (HES).
* The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). The patient has other pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis).
* The patient is a current smoker (ie, has smoked within the last 6 months prior to screening).
* The patient has a history of use of systemic immunosuppressive or immunomodulating agents (anti-IgE mAb, methotrexate, cyclosporin, interferon-α, or anti-tumor necrosis factor mAb) within 6 months prior to study entry (screening).
* The patient is currently using systemic corticosteroids (includes use of oral corticosteroids).
* The patient has a current infection or disease that may preclude assessment of asthma.
* The patient is expected to be poorly compliant with study drug administration, study procedures, or visits.
* The patient has any aggravating factors that are inadequately controlled (eg, gastroesophageal reflux disease).
* 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 90 days prior to screening.
* The patient has previously received anti-hIL-5 monoclonal antibody (eg, mepolizumab).
* Female patients who are pregnant, or nursing, or, if of childbearing potential and not using a medically accepted, effective method of birth control (e.g. spermicide, abstinence, IUD, or steroidal contraceptive \[oral, transdermal, implanted, and injected\]) are excluded from this study.
* The patient has a current infection or disease that may preclude assessment of asthma.
* The patient has a history of concurrent immunodeficiency (human immunodeficiency, acquired immunodeficiency syndrome, or congenital immunodeficiency). Patients in Argentina must have documented serology testing for HIV performed during screening.
* Other exclusion criteria apply.
B: 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
C: Inclusion Criteria:

* Weight between 50 and 125 kg
* Mild, stable allergic asthma
* History of episodic wheeze and shortness of breath
* FEV1 at baseline ≥ 70% of the predicted value
* For women of childbearing potential, agreement to use an effective means of contraception while enrolled in the study
* For men with partners of childbearing potential, willingness to use condoms with spermicide during treatment
* Ability to comprehend and follow all required study procedures
* Positive skin prick test to common aeroallergens (e.g., cat, dust, mite, grass, and pollen)
* Positive allergen-induced early and late airway bronchoconstriction

Exclusion Criteria:

* A worsening of asthma or a respiratory tract infection within 6 weeks preceding study entry
* Acute infection (including viral infection) within the 6 weeks preceding dosing (8 weeks for respiratory infections) or any ongoing chronic infection
* History of recurrent bacterial infection as an adult or history or presence of any chronic infectious condition, including (but not limited to), tuberculosis, parasitic infection, etc.
* Lung disease other than mild allergic asthma
* History of heart, lung, kidney, liver, neurologic or chronic infectious disease
* Concomitant disease or condition, which could interfere with the conduct of the study, including, but not limited to, cancer, alcoholism, drug dependency or abuse, or psychiatric disease
* History of serious adverse reaction or hypersensitivity to any drug
* Pregnancy or lactation or positive serum pregnancy test at screening
* Chronic use of any other medication for treatment of allergic lung disease other than short-acting β2-agonists or ipratropium bromide
* Current (or history of) treatment with a monoclonal antibody or chimeric biomolecule within the past 5 months (5 half-lives of the drug), including omalizumab
* Regular use of tobacco products of any kind or within the previous 6 months, or smoking history \> 10 pack-years
D: Inclusion Criteria:

1. Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a history of physician-diagnosed asthma requiring treatment with medium-to-high dose Inhaled Corticosteroids (ICS) plus asthma controller, for at least 12 months prior to Visit 1.
2. Documented current treatment with high daily doses of ICS plus at least one other asthma controller for at least 3 months prior to Visit 1.
3. History of at least 2 asthma exacerbations while on ICS plus another asthma controller that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit 1.
4. ACQ6 score ≥1.5 at Visit 1.
5. Screening pre-bronchodilator (pre-BD) FEV1 of \<80% predicted at Visit 2.
6. Excessive variability in lung function by satisfying ≥ 1 of the following criteria:

   1. Airway reversibility (FEV1 ≥12%) using a short-acting bronchodilator demonstrated at Visit 2 or Visit 3.
   2. Airway reversibility to short-acting bronchodilator (FEV1 ≥12%) documented during the 12 months prior to enrolment Visit 1.
   3. Daily diurnal peak flow variability of \>10% when averaged over 7 continuous days during the study run-in period
   4. An increase in FEV1 of ≥12% and 200 mL after a therapeutic trial of systemic corticosteroid (eg, OCS), given outside of an asthma exacerbation, documented in the 12 months prior enrolment Visit 1.
   5. Airway hyper-responsiveness (methacholine: PC20 of \<8 mg/mL, histamine: PD20 of \<7.8 μmol, mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 24 months prior to randomization Visit 4.
7. Peripheral blood eosinophil count either:

   * 300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2

OR

≥150 to \<300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2, IF ≥1 of the following 5 clinical criteria (a to e) is met:

1. Using maintenance OCS (daily or every other day OCS requirement in order to maintain asthma control; maximum total daily dose 20 mg prednisone or equivalent) at screening
2. History of nasal polyposis
3. Age of asthma onset ≥18 years
4. Three or more documented exacerbations requiring systemic corticosteroid treatment during the 12 months prior to screening
5. Pre-bronchodilator forced vital capacity \<65% of predicted, as assessed at Visit 2 (note that screening pre-BD FEV1 Inclusion Criterion #6 must still be satisfied)

For inclusion in the open label ANDHI IP sub study patients should meet the following criteria:

1. Patients study must have completed ANDHI EOT Visit 11.
2. Written informed consent must also be obtained prior to any study related procedures being performed in the open label ANDHI IP sub study.
3. Patients who have received any approved or investigational targeted biologic for the treatment of asthma (e.g. commercial mepolizumab, reslizumab, benralizumab) may be included if the last dose is ≥ 2 months of Visit 13.

Exclusion Criteria:

1. Clinically important pulmonary disease other than asthma
2. Acute upper or lower respiratory infections within 30 days prior to the date informed consent.
3. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to, standard of care therapy.
4. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
5. A history of known immunodeficiency disorder.
6. Current smokers or former smokers with a smoking history of ≥10 pack years.
7. Previously received benralizumab (MEDI-563).
8. Receipt of any investigational medication as part of a research study within approximately 5 half-lives prior to randomization.
9. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
10. Receipt of live attenuated vaccines 30 days prior to the date of randomization; other types of vaccines are allowed.
11. Concurrent enrolment in another interventional or post-authorization safety study

Exclusion criteria for the open label ANDHI IP sub study:

Patients should not enter the open label ANDHI IP sub study if any of the following exclusion criteria are fulfilled. Each exclusion criterion should be reviewed in all potential participants, including those who transition directly from the double-blind period and those with a delay between completing the EOT Visit 11 and the first open label visit (Visit 13).

1. Patients who participated in the double-blind period but failed to complete the ANDHI EOT Visit 11. Patients who completed the ANDHI FU Visit 12 are not excluded from participation in the ANDHI IP sub study.
2. Unable to commit to the monthly visits as required by the protocol, or unable to commit to undergoing protocol guided reductions in asthma therapy, as directed by the Investigator.
3. Patients who experienced a severe or serious treatment-related AE during the double-blind period and, and those whom Investigator judges it is not in the patient's best interest to extend possible treatment with benralizumab.
4. Approved or off-label use of systemic immunosuppressive medications within 3 months prior to the first open label visit (Visit 13). These include but are not limited to small molecules such as methotrexate, cyclosporine, azathioprine, and immunosuppressive/immunomodulating biologics such as tumour necrosis factor (TNF) blockers. Regular use of systemic OCS is also excluded except for the indication of asthma.
5. Receipt of live attenuated vaccines 30 days prior to the first visit in the open label ANDHI IP sub study (Visit 13); other types of vaccines are allowed.
6. Planned surgical procedures during the conduct of the study.
7. Positive urine pregnancy test at Visit 13, or currently breastfeeding or lactating women.

Answer: D