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    EudraCT Number:2019-004638-40
    Sponsor's Protocol Code Number:D3250C00025
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-02-14
    Trial results
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    A. Protocol Information
    A.2EudraCT number2019-004638-40
    A.3Full title of the trial
    An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children with Severe Eosinophilic Asthma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to check if benralizumab is safe and tolerated by children with for severe uncontrolled asthma.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD3250C00025
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZenenca AB
    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 supportAstraZenec AB
    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/ cityN/A
    B.5.3.3Post codeN/A
    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 No
    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
    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 typeup to
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 No
    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 Yes
    D. medicinal product typeMonoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Eosinophilic Asthma
    E.1.1.1Medical condition in easily understood language
    Severe Asthma
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10068462
    E.1.2Term Eosinophilic asthma
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To evaluate the pharmacokinetics (PK) of benralizumab administered subcutaneously (SC) in children from 6 to 11 years of age with severe eosinophilic asthma
    -To evaluate the pharmacodynamics (PD) of benralizumab administered SC in children from 6 to 11 years of age with severe eosinophilic asthma
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    -To characterize the PK of benralizumab
    -To evaluate the immunogenicity of benralizumab
    -To evaluate the effect of benralizumab on pulmonary function
    -To assess the effect of benralizumab on asthma symptoms and other asthma control metrics
    Safety objective:
    -To assess the safety and tolerability of benralizumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Parent(s)/guardian are able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. If applicable, the participant must be able and willing to give assent to take part in the study according to the local requirement.
    2.Patient must be 6 to 11 years of age inclusive (6 to 14 years of age inclusive in Japan), at the time of signing the ICF.
    3.Diagnosis of severe asthma, defined by the regional guidelines (ie, National Institutes of Health [NIH], Global Initiative for Asthma [GINA], American Thoracic Society [ATS], European Respiratory Society [ERS], Japanese Society of Pediatric Allergy and Clinical Immunology [JSPACI], etc.), for at least 12 months prior to Visit 1. If the patient is naïve to the study site, the participant/guardian must self-report a physician diagnosis of asthma and the investigator must confirm by review of medical history with the participant/guardian.
    4.A previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids* and/or hospitalization in the 12 months prior to Visit 1, despite the use of ICS, or a persistent need for oral corticosteroid maintenance treatment to maintain asthma control, for at least 3 of the last 12 months prior to Visit 1, despite the use of ICS. *For patients receiving maintenance oral corticosteroids, the OCS treatment for the exacerbations must have been a two-fold increase or greater in the dose.
    5.Eosinophilic airway inflammation that is related to asthma characterized as eosinophilic in nature as indicated by peripheral blood eosinophil count of ≥150 cells / µL at Visit 1.
    6.A well-documented requirement for regular treatment with ICS: total daily dose equivalent to ≥250 µg fluticasone propionate, or ≥400 µg budesonide (≥320 µg budesonide ex-actuator), or ≥200 µg fluticasone furoate, or ≥220 µg mometasone furoate, or ≥160 µg ciclesonide, or ≥1000 µg triamcinolone acetonide, or ≥500 µg beclomethasone dipropionate, or ≥200 µg beclomethasone dipropionate (HFA) in the 12 months prior to Visit 1, with or without maintenance oral corticosteroids. Medium dose ICS as per local guidelines will also satisfy the inclusion criterion after agreement with the Study Physician.
    7.Current treatment with at least 1 additional controller medication, such as inhaled LABA, leukotriene receptor antagonist, long acting anti-muscarinic agent, or theophylline, since at least 3 months prior to Visit 1.
    8.Forced expiratory volume in 1 second (FEV1): Flow/ volume curve indicating airflow obstruction at either Visit 1 or 2 (performed prior to first dose of study medication), associated with: a pre-bronchodilator FEV1 ≤ 110% predicted normal, or, FEV1/Forced Vital Capacity ratio ≤ 0.8.
    9.Body weight ≥15 kg.
    10.Male or female
    11.Females of childbearing potential (FOCBP) who are sexually active, as judged by the investigator, must commit to consistent and correct use of an acceptable method of contraception for the duration of the study and for 4 months after the last dose of IP.
    E.4Principal exclusion criteria
    1.Any history of life-threatening asthma (eg, requiring intubation)
    2.Clinically important pulmonary disease other than asthma such as active lung infection, bronchiectasis, pulmonary fibrosis, cystic fibrosis, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia
    3.Previous diagnosis of pulmonary or systematic disease, other than asthma, that is associated with elevated peripheral eosinophil counts such as allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and hypereosinophilic syndrome
    4.Ever been diagnosed with malignant disease
    5.Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, immunological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could:Affect the safety of the patient throughout the study, Influence the findings of the study or their interpretations, Impede the patient’s ability to complete the entire duration of the study
    6.History of anaphylaxis to any biologic therapy
    7.Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during 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
    8.Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening period, which in the opinion of the investigator may put the patient at risk or interfere with study assessments
    9.Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol
    10.A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed consent and assent is obtained that has not been treated with, or has failed to respond to, standard of care therapy
    11.Alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit of normal confirmed during the screening period
    12.A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test
    13.Use of immunosuppressive medication, including, but not limited to, methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy, within 3 months prior to Visit 1. Chronic maintenance corticosteroid for the treatment of asthma is allowe.
    14.Receipt of immunoglobulin or blood products within 30 days prior to Visit 1
    15.Receipt of any marketed (eg, omalizumab, mepolizumab, or off-label benralizumab) or investigational biologic within 4 months or 5 half-lives, whichever is longer, prior to Visit .
    16.Receipt of live attenuated vaccines 30 days prior to the date of first dose of IP
    17.Initiation of new allergen immunotherapy is not allowed within 30 days prior to Visit 1.However, allergen immunotherapy initiated prior to this period can be continued provided there is a gap of 7 days between the immunotherapy and IP administration.
    18.Current use of any oral or ophthalmic non-selective β-adrenergic antagonist (eg, propranolol)
    19.Planned surgical procedures during the conduct of the study
    20.Participation in another clinical study with an investigational nonbiologic product administered in the last 30 days or 5 half-lives prior to enrolment, whichever is longer
    21.Known history of allergy or reaction to any component of the IP formulation
    22.Concurrent enrolment in another clinical study
    23.Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (eg, inability to read, comprehend and write) which will limit the validity of consent to participate in this study
    24.Unwillingness or inability of the participant or parent/guardian to follow the procedures outlined in the protocol
    25.Children who are wards of the state or government
    26.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
    27.Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
    28.Previous treatment in the present study
    E.5 End points
    E.5.1Primary end point(s)
    1.To evaluate pharmacokinetics of benralizumab administered subcutaneously in children from 6-11 year of age with severe eosinophilic asthma:
    •Area under concentration time curve to Day 28 (AUC0-28)
    •Maximum serum concentration (Cmax)
    •Terminal phase elimination half-life (t1/2)
    •Time to reach Cmax (Tmax)
    2.To evaluate pharmacodynamics of benralizumab administered subcutaneously in children from 6-11 year of age with severe eosinophilic asthma:
    •Change from baseline in peripheral blood eosinophil count
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.To evaluate pharmacokinetics at visit 2(day 0), visit 3(day 1), visit 4(day 7), visit 5(day 14), visit 6(day 28), visit 7(day 56), visit 8(day 84), visit 9(day112), visit 10(day 168), visit 13(336).
    2.To evaluate pharmacodynamics at visit 1(day -28 to -14), visit 6(day 28), visit 7(day 560), visit 8(day 84), visit 9(day 112), visit 10(day 168), visit 13(day 336)
    E.5.2Secondary end point(s)
    -Body weight-adjusted clearance
    -Presence of anti-benralizumab antibodies
    -Change from baseline in pre-dose (when applicable), pre-bronchodilator, forced expiratory volume in 1 second (FEV1) measured at Weeks 4, 8, 12, and 16 (Part A), and Weeks 24 and 48 (Part B)
    -Change from baseline in Interviewer-administered Asthma Control Questionnaire (ACQ-IA) score, measured at screening and Weeks 1, 2, 4, 8, 12, and 16 (Part A), and Weeks 24, 32, 40 and 48, and at follow-up (Part B)
    Interviewer-administered Patient Global Impression of Change (PGIC-IA), measured at Week 16 (Part A), Weeks 24, 32 and 48 (Part B), and at the DXD/WD visit
    Clinician Global Impression of Change (CGIC), measured at Week 16 (Part A), Weeks 24, 32 and 48 (Part B), and at the DXD/WD visit
    -Vital signs
    -Collection of clinical chemistry/haematology parameters and urinalysis
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Body weight-adjusted clearance at day 0,day 1,day 7,day 14,day 28,day 56,day 84,day 112,day 168,day 336
    -Presence of anti-benralizumab antibodies at day 0,day 56, day 112,day 168,day 336
    -Change from baseline in pre-dose, pre-bronchodilator, forced expiratory volume in 1 second at day -28 to -14,day 0,day 28,day 56,day 84,day112,day 168,day 336
    -Change from baseline in Interviewer-administered Asthma Control Questionnaire score at day -28 to -14,day 0,day 7,day 14,day 28,day 56,day 84,day112,day 168,day224,day 280,day 336,day 362
    - PGIC-IA and CGIC are measured at day 112,day 168,day 224,day 336
    -AEs and Vital sings from day -28 to -14 to day 362
    -Collection of clinical chemistry/haematology parameters and urinalysis at day -28 to -14,day 28, day 56,day 84,day112,day 168,day 336
    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 No
    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. 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    United States
    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.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days3
    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: 33
    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) Yes
    F. of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 3
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 33
    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)
    The patient should continue their usual asthma medication at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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