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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Hypereosinophilic Syndrome
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Recruiting
    • Research Site
• Belgium
  • Brussels, Belgium, 1070
    • Recruiting
    • Research Site
  • Edegem, Belgium, 2650
    • Recruiting
    • Research Site
  • Leuven, Belgium, 3000
    • Recruiting
    • Research Site
• Denmark
  • København Ø, Denmark, 2100
    • Recruiting
    • Research Site
• France
  • Lille Cedex, France, 59037
    • Recruiting
    • Research Site
  • PARIS Cedex 12, France, 75571
    • Recruiting
    • Research Site
  • Pessac, France, 33604
    • Recruiting
    • Research Site
  • Strasbourg, France, 67091
    • Recruiting
    • Research Site
  • Suresnes Cedex, France, 92151
    • Recruiting
    • Research Site
  • Toulouse Cedex 9, France, 31059
    • Recruiting
    • Research Site
• Germany
  • Hannover, Germany, 30625
    • Recruiting
    • Research Site
  • Kirchheim, Germany, 73230
    • Completed
    • Research Site
  • Mannheim, Germany, 68167
    • Recruiting
    • Research Site
• India
  • Ahmedabad, India, 380013
    • Recruiting
    • Research Site
  • Ajmer, India, 305001
    • Recruiting
    • Research Site
  • Delhi, India, 110029
    • Recruiting
    • Research Site
  • Nagpur, India, 440012
    • Recruiting
    • Research Site
• Israel
  • Haifa, Israel, 34362
    • Recruiting
    • Research Site
  • Holon, Israel, 58100
    • Recruiting
    • Research Site
  • Jerusalem, Israel, 91120
    • Active, not recruiting
    • Research Site
  • Kfar Saba, Israel, 44218
    • Recruiting
    • Research Site
  • Petah Tiqva, Israel, 49100
    • Recruiting
    • Research Site
  • Ramat Gan, Israel, 5265601
    • Completed
    • Research Site
  • Rehovot, Israel, 76100
    • Recruiting
    • Research Site
  • Tel-Aviv, Israel, 64239
    • Recruiting
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • Research Site
  • Milano, Italy, 20132
    • Recruiting
    • Research Site
• Japan
  • Bunkyo-ku, Japan, 113-8431
    • Recruiting
    • Research Site
  • Chiba-shi, Japan, 260-0852
    • Recruiting
    • Research Site
  • Hamamatsu-shi, Japan, 431-3192
    • Recruiting
    • Research Site
  • Ichikawa-shi, Japan, 272-8516
    • Recruiting
    • Research Site
  • Kawasaki-shi, Japan, 211-8510
    • Recruiting
    • Research Site
  • Nishinomiya-shi, Japan, 663-8501
    • Recruiting
    • Research Site
  • Osaka-shi, Japan, 530-8480
    • Recruiting
    • Research Site
  • Sendai-shi, Japan, 980-8574
    • Recruiting
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 5505
    • Recruiting
    • Research Site
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Recruiting
    • Research Site
• Poland
  • Chęciny, Poland, 26-060
    • Recruiting
    • Research Site
  • Gdańsk, Poland, 80-214
    • Recruiting
    • Research Site
  • Łódź, Poland, 90-153
    • Recruiting
    • Research Site
• Spain
  • Salamanca, Spain, 37007
    • Recruiting
    • Research Site
  • Santander, Spain, 39010
    • Recruiting
    • Research Site
• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Research Site
  • Zürich, Switzerland, 8091
    • Withdrawn
    • Research Site
• United Kingdom
  • London, United Kingdom, W2 1NY
    • Recruiting
    • Research Site
• United States
  • California
    • La Jolla, California, United States, 92037
      • Recruiting
      • Research Site
    • Newport Beach, California, United States, 92663
      • Recruiting
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30324
      • Recruiting
      • Research Site
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Recruiting
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Recruiting
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Research Site
    • Columbus, Ohio, United States, 43212
      • Recruiting
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Recruiting
      • Research Site
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98115
      • Recruiting
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 130 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. 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
2. Males and females 12 years of age and older at the time of signing the ICF
3. 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)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
5. Stable HES treatment dose(s) and regimen for ≥ 4 weeks at the time of Visit 1

6. 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

7. AEC ≥ 1000 cells/μL at Visit 1 (assessed by local laboratory)
8. 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

9. 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:

   1. Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
   2. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
   3. Intrauterine device
   4. Intrauterine hormone-releasing system
   5. Bilateral tubal occlusion
   6. 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)
   7. 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

1. Life-threatening HES and/or HES complication(s) as judged by the investigator:

   1. Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization
   2. 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
   3. 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

   1. 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
   2. 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:

   1. 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
   2. Patients with basal cell or superficial squamous skin cancer
   3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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
Time to first haematologic relapse	A haematologic relapse is defined as AEC ≥1000 cells/μL	Up to 24 weeks
Proportion of patients who experience HES worsening/flare		Up to 24 weeks
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
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
number of HES worsenings/flares	Number of HES worsenings/flares (annualised rate/year) during the DB period	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 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
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

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• The study website.
• This is a one-page brochure on Natron study.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2020
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): November 20, 2026

Study Registration Dates

• First Submitted: November 20, 2019
• First Submitted That Met QC Criteria: December 5, 2019
• First Posted (Actual): December 9, 2019

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: benralizumab; Hypereosinophilic Syndrome (HES)
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Hematologic Diseases; Leukocyte Disorders; Eosinophilia; Syndrome; Hypereosinophilic Syndrome; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: D3254C00001; 2019-002039-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No