A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients with Hypereosinophilic Syndrome (HES) - NATRON

Exclusion Criteria

• 1. Life-threatening HES and/or HES complication(s) as judged by the investigator:
• a. Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization
• b. History of thrombotic complications, stroke, or significant cardiac damage related to HES, if the respective events were life threatening and currently represent a risk of life-threatening disease complications. Events that occurred in the past but considered resolved or stable, can be accepted if, as per investigator’s judgment, participation in the study will not put the patient at risk
• c. Disease severity that in the opinion of the investigator makes the patient inappropriate for inclusion in the study
• 2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
• 3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
• 4. Known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment 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 the entire duration of the study
• 5. Hypereosinophilia of unknown significance
• 6. Cardiovascular: Documented history of any clinically significant cardiac damage, clinically significant echocardiography (if available) or ECG findings within 12 months prior to Visit 1 or clinically significant ECG findings at screening that in the opinion of the investigator may put the patients at risk
• 7. Known currently active liver disease
• a. Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen or hepatitis C antibody) or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis
• b. ALT or AST level ≥ 3 × ULN during the screening period (AST or ALT > 5 × ULN if documented HES with liver manifestations). Transient increase of AST/ALT level that resolves by the time of randomisation is acceptable if, in the investigator’s opinion, the patient does not have an active liver disease and meets other eligibility criteria
• 8. Current or history of malignancy within 5 years before the screening visit with the following exceptions:
• a. Patients treated for in situ carcinoma of the cervix who have completed curative therapy and are in remission for at least 12 months prior to signing the informed consent and
• b. Patients with basal cell or superficial squamous skin cancer
• c. 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
• 9. Diagnosis of systemic mastocytosis
• 10. Chronic or ongoing active infections requiring systemic treatment, as well as clinically significant viral, bacterial, or fungal infection within 4 weeks prior to Visit 1
• 12. A history of known immunodeficiency disorder other than that explained by the use of OCS or other therapy taken for HES. Positive HIV test
• 14. Evidence of prior benralizumab treatment failure