Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase IIIb Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Xolair in Subjects With Moderate to Severe Persistent Asthma Who Are Inadequately Controlled With High-Dose Inhaled Corticosteroids and Long-Acting Beta-Agonists
Brief Summary: This is a multicenter, randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of subcutaneously administered Xolair as add-on therapy for the treatment of subjects aged 12-75 years old diagnosed with moderate to severe asthma who are inadequately controlled with high-dose inhaled corticosteroids (ICS)+ long-acting beta-agonists (LABA) with or without additional controller therapy.


Options:
A: Inclusion Criteria:

* Males or females 18 to 65 years of age at the time of screening
* Baseline percent of predicted FEV1 ≥ 50% to ≤ 80% at screening
* At least 12% reversibility over baseline FEV1 with beta agonist inhalation, which can be demonstrated in the office or documented by medical record within the past 12 months
* Inhaled corticosteroid (ICS) ≥ 200 and ≤ 1000 µg/day fluticasone or equivalent. Stable ICS dose for ≥ 30 days before screening and dose expected to remain stable during treatment with investigational agent. Must have used ICS for at least the last 3 consecutive months before screening
* If receiving allergen immunotherapy, a stable dose for \> 3 months before screening and anticipated to remain stable for the duration of the study
* Positive to skin prick or RAST
* Ongoing asthma symptoms with ACQ score at screening and baseline ≥ 1.5 points
* Nonsmoker or ex-smoker with \< 10 pack-years (eg, 1 pack per day for 10 years) who stopped ≥ 1 year ago

Exclusion Criteria:

* Acute asthma exacerbation requiring emergency room (ER) treatment or hospitalization within 3 months
* History of endotracheal intubation for asthma-related exacerbation within 3 years of screening
* Respiratory illness within 4 weeks of screening
* History of chronic obstructive pulmonary disease (COPD) or other chronic pulmonary condition other than asthma
* Received long-acting beta agonist, theophylline, inhaled anticholinergics, oral beta 2 agonists, or cromolyn therapeutics within 1 week of first run-in visit.
* Leukotriene antagonists within 2 weeks before first run-in visit
* Oral or parenteral corticosteroids within 6 weeks before first run-in visit
* Live/attenuated vaccinations within 4 weeks of screening or during the study
* Any uncontrolled, clinically significant systemic disease (eg, chronic renal failure, uncontrolled hypertension, liver disease)
B: Inclusion Criteria:

* Signed Informed Consent Form and an informed assent, if applicable
* Be between the ages of 12 to 75 years
* Have had a history of moderate to severe asthma for at least one year prior to screening
* Have had treatment with a stable regimen of of salmeterol 50 µg twice a day (BID) or formoterol 12 µg BID for at least 8 weeks prior to screening
* Have had treatment with a stable regimen of high-dose inhaled corticosteroids (ICS) for at least 8 weeks prior to screening
* Have inadequately controlled asthma
* Have had at least one asthma exacerbation requiring systemic corticosteroid rescue in the 12 months prior to the screening visit while receiving treatment with high-dose ICS
* Have less than 10 pack-years smoking history
* Have a positive skin test for or a positive, in vitro response to one relevant perennial aeroallergen documented within the 12 months prior to screening
* If a subject has not had a positive skin test or in vitro reactivity in the 12 months prior to screening, the subject must demonstrate a positive response to at least one relevant perennial aeroallergen in a skin or in vitro test prior to randomization
* Female subjects of childbearing potential must use an effective method of contraception from screening through their duration of participation in the study
* For the collection of additional blood samples for future research (optional), provide signed consent and an informed assent, if applicable.

Exclusion Criteria:

* Have had an asthma exacerbation requiring intubation within 12 months prior to screening
* Have active lung disease other than asthma
* Have had an asthma exacerbation requiring treatment with the addition of systemic (oral or intravenous) corticosteroids or an increase in systemic corticosteroids within 30 days prior to screening
* Require chronic immunosuppressive therapy including cyclosporine, methotrexate, etc.
* Have significant medical illness other than asthma
* Have taken methotrexate, gold salts, cyclosporine, or macrolide antibiotics, within 3 months prior to screening
* Have taken other investigational drugs within 30 days prior to screening
* Have been treated with Xolair within the 12 months prior to screening
* Have a history of drug or alcohol abuse that, in the judgment of the investigator, may put the subject at risk for being unable to participate fully in the study for the duration of the study
* Have elevated serum IgE levels for reasons other than allergy
* Are pregnant or lactating
C: * INCLUSION CRITERIA:

A subject will be eligible for participation in the study only if all of the following criteria apply:

1. Male or female subject greater than or equal to18 and less than or equal to 75 years of age at screening.
2. A female subject is eligible for this study only if she is not pregnant or breast-feeding and one of the following:

   1. Of childbearing potential but agrees to practice effective contraception, as determined by the PI, or abstinence throughout the study and for 3 months after administration of the last dose of investigational study drug
   2. Of non-child-bearing potential

Females of non-child-bearing potential are defined as females with functioning ovaries with a documented history of tubal ligation or hysterectomy or females who are post-menopausal, as defined by 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, \>45 years, in the absence of hormone replacement therapy. In questionable cases, a blood sample for follicle stimulating hormone and estradiol will be obtained to confirm child-bearing potential.

Acceptable methods of contraception may include one or more of the following:

1) male partner who is sterile prior to the female subject s entry into the study and is the sole sexual partner for the female subject; 2) implants of levonorgestrel; 3) injectable progestogen, 4) an intrauterine device with a documented failure rate of \<1%; and 5) double barrier methods including diaphragm or condom with a spermicide.

3) A male subject is eligible for this study only if he is one of the following:

1. Surgically sterile
2. Agrees to practice effective contraception (see above) or abstinence throughout the study and for 3 months after the last administration of the investigational study drug

   4) Documented diagnosis of HES (history of persistent eosinophilia \>1500/(micro) L without secondary cause and evidence of end organ manifestations attributable to the eosinophilia)

   5) Signs or symptoms of HES and AEC \>1000/(micro) L on stable HES therapy for greater than or equal to 1 month at the time of enrollment

   6) Participation in protocol 94-I-0079 (Activation and function of eosinophils in conditions with blood or tissue eosinophilia)

   7) Agrees to storage of samples for study

   Participation of Women:

   Contraception: The effects of benralizumab on the developing human fetus are unknown. For this reason, men and women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Females of childbearing-age must have a negative pregnancy test result prior to receiving benralizumab. During the course of the study, if a woman becomes pregnant or suspects she is pregnant, she should inform the study staff and her primary care physician immediately. If a subject becomes pregnant, the investigational drug will be discontinued immediately, and the subject will be counselled as to how to resume approved therapeutic options in consultation with an obstetric provider.

   EXCLUSION CRITERIA:

   A subject will be excluded from participation in the study if any of the following criteria apply at the time of enrollment:
   1. Subjects with life-threatening or other serious illness or clinical manifestation of HES deemed inappropriate for inclusion in study per the principal investigator, including but not restricted to severe cardiac involvement and prior thromboembolic disease.
   2. Human immunodeficiency virus (HIV) or other known immunodeficiency
   3. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll
   4. Presence of FIP1L1/PDGFRA or another known imatinib-sensitive mutation
   5. Diagnosis of systemic mastocytosis or serum tryptase level \>40 ng/mL
   6. Known lymphoma, hematological malignancy, advanced and metastatic solid tumors and/or subjects who are under chemotherapy, radiotherapy or interleukin 2 treatment
   7. Known history of allergic or anaphylactic reaction to previous antibody therapy, including intravenous immunoglobulin and licensed or experimental monoclonal antibodies.
   8. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained
   9. Acute bacterial or viral infection (subjects may be enrolled once the acute infection has resolved).
   10. Receipt of intravenous immunoglobulin (IVIG) within 30 days prior to the date informed consent is obtained
   11. Receipt of any marketed (eg omalizumab) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer
   12. Receipt of live attenuated vaccines 30 days prior to the date of randomization
   13. Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed provided they are not administered within 1 week before/after any study visit
   14. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer
   15. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained
   16. Previous treatment with benralizumab (MEDI-563).

   Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than enrollment on observational studies or those evaluating the use of a licensed medication. Study staff should be notified of co-enrollment as it may require the approval of the Investigator.

   Justification for Exclusion of Children:

   Because there are insufficient data regarding dosing or adverse events available in adults with HES to judge the potential risk in children, children are excluded from this study.
D: Inclusion Criteria:

Severe persistent asthma with the following characteristics:

* Uncontrolled according to Global Initiative for Asthma (GINA) 2007 guidelines and at least 2 exacerbations having required systemic corticosteroid and/or at least 1 hospitalization or emergency room visit in the past year.
* Treated with high-dose inhaled corticosteroid (i.e. \> 1,000 µg beclometasone dipropionate equivalent per day) plus inhaled long-acting β2 agonist (with or without maintenance oral corticosteroid).
* Non-atopic, i.e. negative blood multiallergic testing and negative Aspergillus-specific IgE-radio allergosorbent blood test and negative skin prick tests to a battery of common aeroallergens

Exclusion Criteria:

* Current smokers or smoking history stopped for less than 3 years or \> 10 pack years.
* Asthma exacerbation during the 4 weeks prior to randomization.
* Active lung disease other than non-atopic asthma.
* Patients with an active cancer, a suspicion of cancer or any history of cancer with less than 5 disease free years.
* Pregnant or nursing (lactating) women.
* Treatment with omalizumab.

Other protocol-defined inclusion/exclusion criteria may apply

Answer: B