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

Study Overview
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Brief Summary
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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.

Official Title
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A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24 Week Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)

Conditions
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Hypereosinophilic Syndrome

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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: Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable Intrauterine device Intrauterine hormone-releasing system Bilateral tubal occlusion Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient) Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomised partner has received medical assessment of the surgical success) Exclusion Criteria Life-threatening HES and/or HES complication(s) as judged by the investigator: Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization 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 Disease severity that in the opinion of the investigator makes the patient inappropriate for inclusion in the study 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 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 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 Current or history of malignancy within 5 years before the screening visit with the following exceptions: 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 Patients with basal cell or superficial squamous skin cancer 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 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 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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab arm<br>1x Benralizumab SC injection | Biological: Benralizumab<br>* Benralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks<br>|
| Placebo Comparator: Placebo arm<br>1x Benralizumab matching placebo SC injection | Biological: Placebo<br>* Matching placebo solution for injection in an APFS will be administered SC every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first HES worsening/flare | An HES worsening or flare is defined as HES clinical manifestations or lab abnormalities that result in an increase/burst of OCS ≥10 mg/day for at least 2 days, OR an increase or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalisation | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who experience HES worsening/flare |  | Up to 24 weeks | 
| number of HES worsenings/flares | Number of HES worsenings/flares (annualised rate/year) during the DB period | Up to 24 weeks | 
| Time to first haematologic relapse | A haematologic relapse is defined as AEC ≥1000 cells/μL | Up to 24 weeks | 
| Change from baseline in fatigue severity | Patient reported measure of fatigue severity (PROMIS fatigue short form 7a) | at week 24 | 
| Proportion of patients who have haematologic relapse |  | Up to 24 weeks | 
| Proportion of patients who have AEC<500 cells/µL for 24 weeks |  | Up to 24 weeks | 
| Proportion of patients who require an increase in corticosteroid dose | Proportion of patients who require an increase in corticosteroid dose from baseline at any point in the double-blind treatment period | Up to 24 weeks | 
| HRQoL | Derived from the SF-36v2 questionnaires which contains 36 questions measuring patients' general functional health and well-being, both physically and mentally | Up to 24 weeks | 
| PGIS | The PGIS is a single question evaluating patients' perception of overall symptom severity | Up to 24 weeks | 
| PGIC | The PGIC is a single question evaluating whether there has been an improvement or decline in patients' overall health status after start of treatment. | Up to 24 weeks | 
| Serum benralizumab concentration as a measure of pharmacokinetics |  | Up to 24 weeks | 
| Anti-drug antibodies (ADA) titers and neutralizing antibodies (nAb) as measure of immunogenicity |  | Up to 24 weeks | 
| Adverse Events (AEs) as an evaluation of safety and tolerability of benralizumab |  | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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benralizumab, Hypereosinophilic Syndrome (HES)