A Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation

Inclusion criteria

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 aged 18 to 75 years inclusively at the time of Visit 1

3. Documented current treatment with ICS and LABA for at least 30 days prior to Visit 1.
The ICS and LABA can be parts of a combination product or given by separate inhalers.
The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry
powder formulation or equivalent daily. Additional asthma controller medications, eg,
oral corticosteroids, long-acting antimuscarinics (LAMAs), LTRAs, theophylline etc.
are allowed if they have been used for at least 30 days prior to Visit 1

4. History of at least 2 asthma exacerbations that required treatment with systemic
corticosteroids (intramuscular (IM), intravenous (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. Pre-bronchodilator (pre-BD) FEV1 of < 80% predicted at Visit 2 or Visit 3

6. ACQ-6 score ≥1.5 at Visit 1

7. Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 ml)
demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body
plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2
only

8. Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1

9. Women of childbearing potential (WOCBP) must use an effective form of birth control
confirmed by the Investigator. WOCBP must also have negative serum pregnancy test
result on Visit 1.

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. The following agespecific requirements apply:

- Women <50 years old are considered postmenopausal if they have been amenorrheic
for 12 months or more following cessation of exogenous hormonal treatment and
follicle stimulating hormone (FSH) levels in the postmenopausal range.

- Women ≥50 years old are considered postmenopausal if they have been amenorrheic
for 12 months or more following cessation of all exogenous hormonal treatment.

10. 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

11. Weight of ≥40 kg

Additional inclusion criteria applicable for the Body Plethysmography substudy 1.Residual
volume ≥125% of predicted at Visit 3.

Inclusion criteria at randomization visit

1. At least 1 of the following within 7 days prior to randomization:

- Daytime or nighttime asthma symptoms for 2 or more days;

- Rescue SABA use for 2 or more days;

- Nighttime awakenings due to asthma at least 1 night during the 7-day period

2. ACQ >0.75 at Visit 4 prior to randomization.

3. A negative urine pregnancy test in WOCBP prior to administration of IP

Exclusion criteria

1. Clinically important pulmonary disease other than asthma (eg, 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 (eg,
allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome,
hypereosinophilic syndrome)

2. Life-threatening asthma defined as episodes requiring intubation associated with
hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes
within the 12 months prior to Visit 1.

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. An upper respiratory tract infection or an asthma exacerbation that required treatment
with systemic corticosteroids or an increase in regular maintenance dose of OCS during
the screening/run-in period prior to randomization Visit 4

5. 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

6. Known history of allergy or reaction to any component of the investigational product
formulation

7. History of anaphylaxis to any biologic therapy

8. History of Guillain-Barré syndrome

9. 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

10. Any clinically significant abnormal findings in physical examination, vital signs,
hematology, clinical chemistry, or urinalysis 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

11. 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

12. History of alcohol or drug abuse within 12 months prior to the date informed consent
is obtained

13. 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

14. A history of known immunodeficiency disorder including a positive human
immunodeficiency virus (HIV) test

15. 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

16. Current malignancy, or history of malignancy, except for:

- Patients who have had basal cell carcinoma, localized squamous cell carcinoma of
the skin 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 was 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 was obtained.

17. Use of immunosuppressive medication (including but not limited to: oral
corticosteroids [for reasons other than asthma], methotrexate, troleandomycin,
cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any
experimental anti-inflammatory therapy) within 3 months prior to the date informed
consent

18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times
the upper limit of normal (ULN) confirmed during screening period

19. Receipt of immunoglobulin or blood products within 30 days prior to the date informed
consent is obtained

20. Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational biologic
within 4 months or 5 half-lives prior to the date informed consent is obtained,
whichever is longer

21. Receipt of live attenuated vaccines 30 days prior to the date of randomization

22. Receipt of any investigational medication within 30 days or 5 half-lives prior to
randomization, whichever is longer

23. Previously received benralizumab (MEDI-563)

24. Planned surgical procedures during the conduct of the study

25. Currently breastfeeding or lactating women

26. Previous randomization in the present study

27. Concurrent enrolment in another interventional or post-authorization safety study
(PASS).

28. AstraZeneca staff involved in the planning and/or conduct of the study

29. Employees of the study center or any other individuals involved with the conduct of
the study or immediate family members of such individuals

Exclusion criteria at randomization Visit 4

1. Greater than/equal to 20% change in mean Pre BD FEV1 value at randomization Visit 4 from
the mean pre BD FEV1 calculated from the pre BD FEV1 recorded at Visit 2 and Visit 3