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A Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) (NATRON)

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ClinicalTrials.gov Identifier: NCT04191304
Recruitment Status : Recruiting
First Posted : December 9, 2019
Last Update Posted : March 4, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase 3 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 prior stable HES background therapy, and an open-label (OLE) treatment period, during which all patients will receive benralizumab. Patients will not continue to be recruited after 47 patients have had their first HES worsening/flare.The primary database lock (DBL) will occur when at least 47 patients have had their first HES worsening/flare event and all randomised patients have been followed up for the 24-week DB treatment period. The target patient population is male and female patients 12 years of age and older with symptomatic active HES. Approximately 120 eligible patients will be randomised at a 1:1 ratio to receive either benralizumab or matching placebo

Condition or disease Intervention/treatment Phase
Hypereosinophilic Syndrome Biological: Benralizumab Biological: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment
Official Title: A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24-week Phase 3 Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)
Actual Study Start Date : July 20, 2020
Estimated Primary Completion Date : August 26, 2022
Estimated Study Completion Date : August 17, 2023


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




Primary Outcome Measures :
  1. Time to first HES worsening/flare [ Time Frame: Up to 24 weeks ]
    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 in increase or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalisation


Secondary Outcome Measures :
  1. Time to first haematologic relapse [ Time Frame: Up to 24 weeks ]
    A haematologic relapse is defined as AEC ≥1000 cells/μL

  2. Proportion of patients who experience HES worsening/flare [ Time Frame: Up to 24 weeks ]
  3. Proportion of patients who have haematologic relapse [ Time Frame: Up to 24 weeks ]
  4. Proportion of patients who have AEC<500 cells/µL for 24 weeks [ Time Frame: Up to 24 weeks ]
  5. Proportion of patients who require an increase in corticosteroid dose [ Time Frame: Up to 24 weeks ]
  6. Change from baseline in fatigue [ Time Frame: Up to 24 weeks ]
    The PROMIS Fatigue Short Form 7a will be used which contains 7 questions assessing a range of patient-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles

  7. Change from baseline in HRQoL [ Time Frame: Up to 24 weeks ]
    Derived from the SF-36v2 questionnaires which contains 36 questions measuring patients' general functional health and well-being, both physically and mentally

  8. PGIS [ Time Frame: Up to 24 weeks ]
    The PGIS is a single question evaluating patients' perception of overall symptom severity

  9. PGIC [ Time Frame: Up to 24 weeks ]
    The PGIC is a single question evaluating whether there has been an improvement or decline in patients' overall health status after start of treatment.

  10. Serum benralizumab concentration as a measure of pharmacokinetics [ Time Frame: Up to 24 weeks ]
  11. Anti-drug antibodies (ADA) titers and neutralizing antibodies (nAb) testing for all ADA-positive samples as measure of immunogenicity [ Time Frame: Up to 24 weeks ]
  12. Percentage of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 24 weeks ]
  13. Change from baseline in systolic and diastolic blood pressure [ Time Frame: Up to 24 weeks ]
  14. Change from baseline in pulse rate [ Time Frame: Up to 24 weeks ]
  15. Change from baseline in respiratory rate [ Time Frame: Up to 24 weeks ]
  16. Change from baseline in hematology parameters of hemoglobin, leukocytes, lymphocytes, monocytes, basophils, eosinophils, neutrophils, and platelets [ Time Frame: Up to 24 weeks ]
  17. Change from baseline in clinical chemistry parameters of Alanine Aminotransferase (ALT), alkaline phosphatase, Aspartate Aminotransferase (AST), creatinine kinase, direct, indirect and total bilirubin, uric acid, albumin, creatinine and glucose [ Time Frame: Up to 24 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 130 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  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 1 mg/kg/day at Visit 2 (assessed by local laboratory).
  9. Women of childbearing potential (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

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 randomisation OR
    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, pre-existing, 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. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3× the upper limit of normal (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 malignancy, or history of malignancy, except:

    1. Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to the date that informed consent, and assent when applicable, was obtained.
    2. Patients who have had other malignancies are eligible provided the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent, and assent when applicable, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04191304


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, California
Research Site Recruiting
La Jolla, California, United States, 92037-0943
United States, Georgia
Research Site Recruiting
Atlanta, Georgia, United States, 30324-3269
United States, Maryland
Research Site Recruiting
Bethesda, Maryland, United States, 20892
United States, Michigan
Research Site Recruiting
Ann Arbor, Michigan, United States, 48105-9484
United States, Minnesota
Research Site Recruiting
Rochester, Minnesota, United States, 55905-0001
United States, North Carolina
Research Site Recruiting
Durham, North Carolina, United States, 27705
United States, Ohio
Research Site Not yet recruiting
Cleveland, Ohio, United States, 44106
Research Site Recruiting
Columbus, Ohio, United States, 43212
United States, Utah
Research Site Not yet recruiting
Salt Lake City, Utah, United States, 84403
United States, Wisconsin
Research Site Recruiting
Milwaukee, Wisconsin, United States, 53226-4874
Austria
Research Site Recruiting
Innsbruck, Austria, 6020
Belgium
Research Site Recruiting
Brussels, Belgium, 1070
Research Site Recruiting
Edegem, Belgium, 2650
Research Site Not yet recruiting
Leuven, Belgium, 3000
Denmark
Research Site Not yet recruiting
København Ø, Denmark, 2100
France
Research Site Recruiting
Lille Cedex, France, 59037
Research Site Recruiting
Pessac, France, 33604
Research Site Recruiting
Strasbourg, France, 67091
Research Site Recruiting
Suresnes, France, 92151
Germany
Research Site Not yet recruiting
Hannover, Germany, 30625
Research Site Not yet recruiting
Kirchheim, Germany, 73230
Research Site Recruiting
Mannheim, Germany, 68167
Israel
Research Site Recruiting
Haifa, Israel, 34362
Research Site Recruiting
Holon, Israel, 58100
Research Site Recruiting
Jerusalem, Israel, 91120
Research Site Recruiting
Kfar Saba, Israel, 44218
Research Site Recruiting
Petah Tiqva, Israel, 49100
Research Site Recruiting
Ramat Gan, Israel, 52621
Research Site Recruiting
Rehovot, Israel, 76100
Research Site Recruiting
Tel-Aviv, Israel, 64239
Italy
Research Site Recruiting
Bologna, Italy, 40138
Research Site Not yet recruiting
Milano, Italy, 20132
Japan
Research Site Recruiting
Bunkyo-ku, Japan, 113-8431
Research Site Recruiting
Chiba-shi, Japan, 260-0852
Research Site Recruiting
Hamamatsu-shi, Japan, 431-3192
Research Site Recruiting
Ichikawa-shi, Japan, 272-8516
Research Site Recruiting
Kawasaki-shi, Japan, 211-8510
Research Site Recruiting
Nishinomiya-shi, Japan, 663-8501
Research Site Recruiting
Osaka-shi, Japan, 530-8480
Research Site Recruiting
Sendai-shi, Japan, 980-8574
Poland
Research Site Recruiting
Gdansk, Poland, 80-952
Research Site Recruiting
Łódź, Poland, 90-153
Switzerland
Research Site Not yet recruiting
Bern, Switzerland, 3010
Research Site Not yet recruiting
Zürich, Switzerland, 8091
Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04191304    
Other Study ID Numbers: D3254C00001
2019-002039-27 ( EudraCT Number )
First Posted: December 9, 2019    Key Record Dates
Last Update Posted: March 4, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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 request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Statistical Analysis Plan (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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
benralizumab
Hypereosinophilic Syndrome (HES)
Additional relevant MeSH terms:
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Hypereosinophilic Syndrome
Syndrome
Disease
Pathologic Processes
Eosinophilia
Leukocyte Disorders
Hematologic Diseases
Benralizumab
Anti-Asthmatic Agents
Respiratory System Agents