Efficacy and Safety Study of Benralizumab to Reduce OCS Use in Patients With Uncontrolled Asthma on High Dose Inhaled Corticosteroid Plus LABA and Chronic OCS Therapy

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)

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.

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