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    Summary
    EudraCT Number:2019-002039-27
    Sponsor's Protocol Code Number:D3254C00001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-11-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2019-002039-27
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate if benralizumab may be beneficial in the treatment of Hypereosinophilic Syndrome (HES)
    A.3.2Name or abbreviated title of the trial where available
    NATRON
    A.4.1Sponsor's protocol code numberD3254C00001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/035/2022
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZenecaAB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post codeSE-151 85
    B.5.3.4CountrySweden
    B.5.4Telephone number46701010974
    B.5.6E-mailinformation.center@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fasenra
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namebenralizumab
    D.3.2Product code MEDI-563
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNbenralizumab
    D.3.9.1CAS number 1044511-01-4
    D.3.9.2Current sponsor codeMEDI-563
    D.3.9.3Other descriptive namebenralizumab
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypereosinophilic Syndrome (HES)
    E.1.1.1Medical condition in easily understood language
    Hypereosinophilic Syndrome (HES)
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of benralizumab on the time to first HES worsening/flare
    E.2.2Secondary objectives of the trial
    For DB period to evaluate the effect of benralizumab on:
    - the proportion of patients who experience an HES worsening/flare
    - the number of HES worsenings/flares
    - time to first haematological relapse
    - patient reported measure of fatigue
    - the proportion of patients with haematologic relapse
    - the number of patients who maintain AEC < 500 cells/μL for 24 weeks
    - corticosteroid use
    - health status/HRQoL measures

    And also to evaluate the PK, immunogenicity, safety and tolerability of benralizumab in patients with HES

    For OLE extension period to evaluate the effect of benralizumab on:
    - the proportion of patients who experience an HES worsening/flare and on the number of HES worsening/flare (a)
    - patient reported measure of fatigue (b)
    - HRQoL (c)
    (a) Applicable to full duration of OLE
    (b) for HES worsening/flare
    (c) Applicable to 1st year of OLE only
    And also the safety, tolerability, PK and immunogenicity of benralizumab in patients with HES (a)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Mechanistic sub-study: To support identifying predictors and mechanisms of response to benralizumab in adults. The additional exploratory analyses will be performed from three whole blood samples:
    - for DNA analysis to determine clinical subtype of HES by targeted PCR (all study sites).
    - for more in-depth phenotyping of lymphocytes and other leukocytes by flow cytometry of peripheral blood mononuclear cells (PBMC) (all study sites).
    - for phenotyping of eosinophils by flow cytometry (only selected mechanistic sub-study sites)

    Patient qualitative interview sub-study: to characterise the impact of HES on patients´lives and their experiences with the study treatment (selected sites only).
    E.3Principal 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.
    -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
    10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for ≥12 months prior to the planned date of enrolment without an alternative medical cause
    E.4Principal exclusion criteria
    1. Life-threatening HES and/or HES complication(s) as judged by the Investigator:
    (a) Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization, (b) 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 c) 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
    (a) 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
    (b) ALT or AST level ≥3 x 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:
    (a) 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
    (b) Patients with basal cell or superficial squamous skin cancer.
    (c) 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
    11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not been treated or has failed to respond to standard of care therapy. A confirmation of a complete resolution of any helminth parasitic infection prior to Visit 1 should be available
    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.
    13. Any clinically significant abnormal findings in HES physical examination, vital signs, haematology or clinical chemistry during the screening period, 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.
    14.For women only: Currently pregnant, breastfeeding, or lactating women
    15.Treatment with injectable (SC, IV, or IM) corticosteroids in the 4-week period prior to randomisation
    E.5 End points
    E.5.1Primary end point(s)
    Time to first HES worsening/flare
    - Population b: Full analysis set
    - Intercurrent event strategy b: Included in analysis regardless of treatment discontinuation (treatment policy)
    - Population-level summary: Hazard ratio
    (HES worsening/flare: HES clinical manifestations or lab abnormalities that result in an increase/burst of oral corticosteroids (OCS) ≥10 mg/day for at least 2 days OR an increase, or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalization)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the 24wk double-blind treatment period
    E.5.2Secondary end point(s)
    DB treatment period
    - Key: Proportion of patients who experience an HES worsening/flare during the DB period
    - Key: Number of HES worsenings/flares (annualised rate/year) during the DB period
    - Key: Time to first haematologic relapse (AEC ≥ 1000 cells/μL) during the DB period
    - Key: Fatigue severity (PROMIS fatigue short form 7a) at Week 24
    - Proportion of patients who:
    - have haematologic relapse during the DB period
    - have AEC < 500 cells/μL for 24 weeks
    - require an increase in corticosteroid dose from baseline at any point in the DB treatment period
    - HRQoL (SF-36v2, PGIS, PGIC)
    - Serum benralizumab concentrations Anti-benralizumab antibodies and nAbs
    - Safety and tolerability will be evaluated in terms of AEs, vital signs, and clinical laboratory assessments

    OLE treatment period
    - Proportion of patients who experience an HES worsening/flare
    - Annualized rate of HES worsening/flare
    - Fatigue (PROMIS fatigue short form 7a)
    - Safety and tolerability will be evaluated in terms of AEs, vital signs and clinical laboratory assessments
    - Serum benralizumab concentrations, anti-benralizumab antibodies and nAbs
    - HES symptom questionnaire
    - HRQoL (SF-36v2)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Varies depending on the endpoint/objective
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Switzerland
    India
    Israel
    Japan
    Korea, Republic of
    United Kingdom
    United States
    Austria
    Belgium
    Denmark
    France
    Germany
    Italy
    Netherlands
    Poland
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study is defined as the last expected visit/contact of the last patient undergoing the
    study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 6
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 108
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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