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

NCT04191304 | Active Not Recruiting Phase 3 DMC FDA Drug

• 3 other identifiers: D3254C000012023-510455-28-002019-002039-27
• Study Type: interventional
• Target: 134
• Locations: 17 countries
• Sites: 51

Brief Summary

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. The primary database lock (DBL) will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for 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.

Conditions

Hypereosinophilic Syndrome

Keywords

benralizumab; Hypereosinophilic Syndrome (HES)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Proportion of patients who experience HES worsening/flare

  Up to 24 weeks

• number of HES worsenings/flares

  Up to 24 weeks

• Time to first haematologic relapse

  Up to 24 weeks

• Change from baseline in fatigue severity

  at week 24

• Proportion of patients who have haematologic relapse

  Up to 24 weeks

Study Arms (2)

Benralizumab arm

EXPERIMENTAL

1x Benralizumab SC injection

Biological: Benralizumab

Placebo arm

PLACEBO COMPARATOR

1x Benralizumab matching placebo SC injection

Biological: Placebo

Interventions

Benralizumab BIOLOGICAL

Benralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks

Benralizumab arm

Placebo BIOLOGICAL

Matching placebo solution for injection in an APFS will be administered SC every 4 weeks

Placebo arm

Eligibility Criteria

• Age: 12 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (51)

Research Site

La Jolla, California, 92037, United States

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Atlanta, Georgia, 30324, United States

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Bethesda, Maryland, 20892, United States

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Ann Arbor, Michigan, 48105, United States

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Durham, North Carolina, 27705, United States

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Cleveland, Ohio, 44106, United States

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Columbus, Ohio, 43212, United States

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Salt Lake City, Utah, 84112, United States

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Rosario, 2000, Argentina

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Innsbruck, 6020, Austria

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Brussels, 1070, Belgium

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Edegem, 2650, Belgium

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Chengdu, 610041, China

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Tianjin, 300020, China

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Xiamen, 361015, China

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Zhengzhou, 450008, China

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København Ø, 2100, Denmark

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Lille, 59037, France

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Pessac, 33604, France

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Strasbourg, 67091, France

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Suresnes, 92151, France

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Toulouse, 31059, France

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Hanover, 30625, Germany

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Kirchheim, 73230, Germany

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Mannheim, 68167, Germany

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Ahmedabad, 380013, India

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Ajmer, 305001, India

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Delhi, 110029, India

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Haifa, 34362, Israel

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Holon, 58100, Israel

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Jerusalem, 91120, Israel

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Kfar Saba, 44218, Israel

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Petah Tikva, 49100, Israel

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Ramat Gan, 5265601, Israel

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Rehovot, 76100, Israel

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Tel Aviv, 64239, Israel

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Bologna, 40138, Italy

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Chiba, 260-0852, Japan

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Hamamatsu, 431-3192, Japan

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Ichikawa-shi, 272-8516, Japan

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Kawasaki-shi, 211-8510, Japan

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Nishinomiya-shi, 663-8501, Japan

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Osaka, 530-8480, Japan

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Sendai, 980-8574, Japan

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Rotterdam, 3015 GD, Netherlands

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Chęciny, 26-060, Poland

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Gdansk, 80-214, Poland

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Lodz, 90-153, Poland

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Seoul, 5505, South Korea

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Santander, 39010, Spain

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London, W2 1NY, United Kingdom

Location

Related Publications (1)

• Ogbogu PU, Roufosse F, Akuthota P, Kuna P, Groh M, Reiter A, Yokota A, Siddiqui SH, Mutsaers PGNJ, Li B, Khoury P, Bahadori LM, Bednarczyk A, Bouma G, Brooks LG, Ferreira J, Grindebacke H, Ho CN, Jain P, Palmer RL, Jison ML, Klion AD; NATRON study group. Benralizumab versus placebo for hypereosinophilic syndrome: a randomized, placebo-controlled phase 3 trial. Nat Med. 2026 Mar 31. doi: 10.1038/s41591-026-04315-8. Online ahead of print.

  PMID: 41917160 DERIVED

MeSH Terms

Conditions

Hypereosinophilic Syndrome

Interventions

benralizumab

Condition Hierarchy (Ancestors)

Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All eligible patients will be centrally randomly assigned in a 1:1 ratio to receive either benralizumab or placebo. Randomisation will be done using an IWRS/IVRS. Benralizumab and placebo will not be visually distinct from each other. All packaging and labelling of the IP will be done in such a way as to ensure blinding for all Sponsor and investigational site staff. Neither the patient nor any of the Investigators or Sponsor staff who are involved in the treatment, clinical evaluation, and monitoring of the patients will be aware of the treatment received. Since benralizumab and placebo are not visually distinct, IP will be handled by an appropriately qualified member of the study team (e.g., pharmacist, Investigator, or designee) at the site.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2019
• First Posted: December 9, 2019
• Study Start: July 20, 2020
• Primary Completion: May 7, 2025
• Study Completion (Estimated): February 28, 2027
• Last Updated: April 2, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

PL (3); FR (5); GB (1); US (8); AR (1); NL (1); CN (4); IN (3); IT (1); BE (2); ES (1); DE (3); DK (1); KR (1); IL (8); AU (1); JP (7)