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

1.Written informed consent for study participation must be obtained prior to
any study related procedures being performed and according to international
guidelines and/or applicable European Union (EU) guidelines.
2.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 ICS plus asthma controller, for at least 12 months prior to
Visit 1. Other acceptable asthma controllers include a long acting
bronchodilator (LABA or long-acting muscarinic antagonists [LAMA]), a
leukotriene inhibitor, theophylline preparations or maintenance OCS (daily or
every other day OCS requirement in order to maintain asthma control; maximum
total daily dose 20 mg prednisone or equivalent).
3.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; see inclusion
criterion 2 for acceptable other asthma controllers.
* For ICS/LABA combination preparations, highest-strength maintenance doses
approved in the given country will meet this criterion.
* If the ICS and the other asthma controller therapies are given by separate
inhalers, then the patient must be on a high daily ICS dose.
4.History of at least 2 asthma exacerbations while on ICS plus another asthma
controller (see inclusion criterion 2 for examples) that required treatment
with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit
1. For patients receiving corticosteroids as a maintenance therapy, the
corticosteroid treatment for the exacerbation is defined as a temporary
increase of their maintenance dose.
5.ACQ6 score *1.5 at Visit 1.
6.Screening pre-bronchodilator (pre-BD) FEV1 of <80% predicted at Visit 2
Note: Spirometry testing should only be performed if the patient meets the
asthma medication hold for lung function testing, the test should be postponed
to another day prior to Visit 3 to improve the chances of achieving a
qualifying FEV1 that is not affected
by bronchodilator medication.
7. Evidence of asthma as documented by excessive variability in lung function
by satisfying *1 of the criteria below: a) Airway reversibility (FEV1 *12%)
using a short-acting bronchodilator demonstrated at Visit 2 or Visit 3. b)
Airway reversibility to short-acting bronchodilator (FEV1
*12%) documented* during the 12 months prior to enrolment Visit 1. c) Daily
diurnal peak flow variability of >10% when averaged over 7 continuous days
during the study run-in period. d) 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. e)
Airway hyper-responsiveness documented in the 24 months prior to randomization
Visit 4.
8. Peripheral blood eosinophil count either: *300 cells/*L assessed by central
laboratory at either Visit 1 or Visit 2 OR *150 to <300 cells/*L assessed by
central laboratory at either Visit 1 or Visit 2, IF *1 of the following 5
clinical criteria (a to e) is met: a) 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. b) History of nasal
polyposis. c) Age of asthma onset *18 years. d) Three or more documented
exacerbations requiring systemic corticosteroid treatment during the 12 months
prior to screening. e) Pre- bronchodilator forced vital capacity <65% of
predicted, as assessed at Visit 2.
9. Women of childbearing potential (WOCBP) must use at least one acceptable and
effective form of birth control (confirmed by the Investigator). Women of
childbearing potential must agree to use birth control, as defined above, from
enrolment, throughout the study duration and until 16 weeks (approximately 5
half-lives) after last dose of investigational product (IP). Women of
childbearing potential must also have negative serum pregnancy test result on
Visit 1.
10.Women not of childbearing potential are defined as women who are either
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy), or who are postmenopausal. Women will be considered
postmenopausal if they have been amenorrheic for 12 months prior to the planned
date of randomization without an alternative medical cause. 11.All male
patients who are sexually active must agree to use a double barrier method of
contraception (condom with spermicide) from the first dose of IP until 16 weeks
after their last dose.
12.Weight of *40 kg.
For Inclusion Criteria for ANDHI in Practice Sub Study please see Page
47 of protocol.

1.Clinically important pulmonary disease other than asthma (eg, active lung
infection, chronic obstructive pulmonary disease [COPD], bronchiectasis,
pulmonary fibrosis, cystic fibrosis), or ever been diagnosed with pulmonary or
systemic disease, other than asthma, that are associated with elevated
peripheral eosinophil counts (eg, allergic
bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome,
hypereosinophilic syndrome).
2.Acute upper or lower respiratory infections within 30 days prior to the date
informed consent is obtained or during the screening/run-in period.
3.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.
4.Known history of allergy or reaction to any component of the IP formulation.
5.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.
6.Any clinically significant abnormal findings in physical examination, vital
signs, hematology, or clinical chemistry during screening 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.
7.Any clinically significant cardiac disease or any electrocardiogram (ECG)
abnormality obtained during the screening/run-in period, which in the opinion
of the Investigator may put the patient at risk or interfere with study
assessments.
8.History of alcohol or drug abuse within 12 months prior to the date informed
consent is obtained.
9.A history of known immunodeficiency disorder including a positive human
immunodeficiency virus (HIV) test.
10.Current smokers or former smokers with a smoking history of *10 pack years.
A former smoker is defined as a patient who quit smoking at least 6 months
prior to Visit 1.
11.Current malignancy, or history of malignancy, except for:
Patients who have had non-melanoma skin cancers or in situ carcinoma of the
cervix are eligible provided that the patient is in remission and curative
therapy was completed at least 12 months prior to the date informed consent is
obtained.
Patients who have had other malignancies are eligible provided that the patient
is in remission and curative therapy was completed at least 5 years prior to
the date informed consent is obtained.
12.Approved or off-label use of systemic immunosuppressive medications within 3
months prior to the date informed consent is obtained. These include but are
not limited to small molecules such as methotrexate, cyclosporine,
azathioprine, and immunosuppressive/immunomodulating biologics such as tumor
necrosis factor (TNF) blockers. Regular use of systemic (oral) corticosteroids
is also excluded except for the indication of asthma.
13.Concurrent biologics for asthma are not allowed except for stable allergen
immunotherapy (defined as a stable dose and regimen at the time of Visit 1).
Acceptable washout periods for other asthma biologics:
Other eosinophil lowering products indicated for asthma (including mepolizumab
or reslizumab): at least 4 months.Prior omalizumab use: at least 1 month.
14.Previously received benralizumab (MEDI-563).
15.Receipt of any investigational medication as part of a research study within
approximately 5 half-lives prior to randomization.
16.ALT or AST level >3 times the upper limit of normal (ULN) confirmed during
screening period.
17.Receipt of immunoglobulin or blood products within 30 days prior to the date
informed consent is obtained.
18.Receipt of live attenuated vaccines 30 days prior to the date of
randomization; other types of vaccines are allowed.
19.Planned surgical procedures during the conduct of the study.
20.Currently breastfeeding or lactating women.
21.Pevious randomization in the present study.
22.Concurrent enrolment in another interventional or post-authorization safety
study.
23.AstraZeneca staff involved in the planning and/or conduct of the study.
24.Employees of the study center or any other individuals involved with the
conduct of the study or immediate family members of such individuals.
For Exclusion Criteria for ANDHI in Practice Sub Study please see Page
50 of protocol.