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This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab versus placebo administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES). This study comprises 2 distinct periods (together defined as the 'main study'): A 24-week, DB treatment period, during which patients will be randomised to receive either benralizumab or placebo, in addition to their prior stable HES background therapy, and an open-label extension (OLE) period, during which all patients will receive benralizumab. Patients will continue to be recruited until approximately 38 patients have had their first HES worsening/flare during the DB treatment period at which point the data cut-off for the primary database lock (DBL) will occur.
Treatment allocation will remain blinded until the primary DBL. After the study is unblinded for the primary analysis, patients and investigators will remain blinded to patients' individual treatment allocations until after the final patient completes the DB treatment period. The primary analysis will only include data from the DB treatment period of the study. A follow-up analysis will be performed once all patients have the opportunity to complete the 24-week DB treatment period. A patient must complete the 24-week DB treatment period on investigational product (IP) to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE.
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Inclusion and exclusion criteria
Inclusion Criteria
Provision of the signed and dated written informed consent of the patient or the patient's legally authorised representative, and informed assent from the patient (per local regulations) prior to any mandatory study-specific procedures, sampling, and analyses
Males and females 12 years of age and older at the time of signing the ICF
Documented diagnosis of HES (history of persistent eosinophilia > 1500 cells/μL without secondary cause on 2 examinations [interval ≥ 1 month; Valent et al 2012] and evidence of end organ manifestations attributable to the eosinophilia)
Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
Stable HES treatment dose(s) and regimen for ≥ 4 weeks at the time of Visit 1
Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative of HES worsening/flare (other than isolated eosinophilia) at Visit 1 OR a documented history of 2 or more HES worsening/flares within 12 months prior to Visit 1 requiring an escalation in therapy
a. At least one flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare
AEC ≥ 1000 cells/μL at Visit 1 (assessed by local laboratory)
Corticosteroid responsiveness defined as an AEC < 1000 cells/μL after a 2-day course of OCS (prednisone/prednisolone) 1 mg/kg/day at Visit 2 (assessed by local laboratory). Other OCSs in equivalent doses are permitted
WOCBP must agree to use a highly effective method of birth control (confirmed by the investigator) from enrolment, throughout the study duration, and within 12 weeks after last dose of IP and have a negative urine dipstick pregnancy test result on Visit 1. Highly effective methods of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include:
Exclusion Criteria
Life-threatening HES and/or HES complication(s) as judged by the investigator:
Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
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
Hypereosinophilia of unknown significance
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
Known currently active liver disease
Current or history of malignancy within 5 years before the screening visit with the following exceptions:
Diagnosis of systemic mastocytosis
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
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
Primary purpose
Allocation
Interventional model
Masking
120 participants in 2 patient groups, including a placebo group
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AstraZeneca Clinical Study Information Center
Data sourced from clinicaltrials.gov
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