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    Summary
    EudraCT Number:2019-001832-77
    Sponsor's Protocol Code Number:D3253C00001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-10-22
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-001832-77
    A.3Full title of the trial
    A Randomized, Double-blind, Active-controlled 52-week Study with an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab compared to Mepolizumab in the treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA) in patients receiving Standard of Care Therapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of Benralizumab in EGPA compared to mepolizumab.
    A.4.1Sponsor's protocol code numberD3253C00001
    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 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 supportAstraZeneca AB
    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/ citySodertalje
    B.5.3.3Post codeSE-151 85
    B.5.3.4CountrySweden
    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 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 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.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration numberDose 1
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 NUCALA
    D.2.1.1.2Name of the Marketing Authorisation holderGSK
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1116
    D.3 Description of the IMP
    D.3.1Product nameNUCALA
    D.3.2Product code L04AC06
    D.3.4Pharmaceutical form Powder for 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 INNMepolizumab
    D.3.9.1CAS number 0196078-29-2
    D.3.9.2Current sponsor codeMepolizumab
    D.3.9.3Other descriptive nameNucala
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    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
    Eosinophilic Granulomatosis with Polyangiitis (EGPA)
    E.1.1.1Medical condition in easily understood language
    Eosinophilic Granulomatosis with Polyangiitis (EGPA)
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    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 assess the durability of response to treatment with benralizumab compared with mepolizumab in patients with relapsing or refractory EGPA who are receiving Standard of Care Therapy, assessed by the proportion of patients in remission at both Weeks 36 and 48.
    Primary endpoint: Proportion of patients with relapsing or refractory EGPA, achieving
    remission, defined as BVAS=0 (BVAS is a physician completed score based on disease activity in multiple parts of the body) and OCS (Oral corticosteroid) dose less or equal to 4mg/day (Main Remission definition) at both weeks 36 and 48.
    Supportive endpoint: Proportion of patients who have achieved remission defined by BVAS =0 and OCS dose less or equal to 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48.
    E.2.2Secondary objectives of the trial
    Double blind period Objectives
    1. To assess the efficacy of benralizumab compared with mepolizumab on duration of clinical remission, defined as accrued duration in weeks where a patient achieves remission 2. To assess the efficacy of benralizumab compared with mepolizumab on time to first relapse. 3. To assess the average daily dose of corticosteroid required during weeks 48 to 52 in patients receiving benralizumab compared to mepolizumab
    4. To assess the annualized relapse rate in patients receiving benralizumab compared to mepolizumab. 5. To assess the proportion of patients who achieve remission within the first 24 weeks and remain in remission for the remainder of the double-blind period in patients receiving benralizumab compared to mepolizumab 6. To assess additional measures of the efficacy and health status/health-related quality of life in patients receiving benralizumab compared to mepolizumab.
    7. To assess the safety and tolerability of benralizumab compared to mepolizum
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Patient Interview Sub-study
    To characterize the patient-reported experience and treatment benefits of benralizumab compared with mepolizumab through patient interviews

    Mechanistic Sub-study
    To evaluate the effect of benralizumab compared to mepolizumab on biomarkers related to the mechanism of action (MoA), eosinophilic
    inflammation and EGPA disease pathogenesis, as well as baseline predictors of response to benralizumab or mepolizumab, through analysis of tissue biopsies and sputum.

    Both sub-studies are part of the main study protocol V1.0, 11Jun2019
    E.3Principal inclusion criteria
    1. Male or female subjects age 18 years or older.
    2. EGPA diagnosis based on history or presence asthma and
    eosinophilia (>1.0x10^9/L and/or >10% of leucocytes) and at least 2
    of; biopsy with eosinophilic vasculitis or perivascular/granulomatous
    inflammation; mono-or polyneuropathy, non-fixed pulmonary infiltrates,
    sino-nasal abnormality; cardiomyopathy; glomerulonephritis; alveolar
    haemorrhage; palpable purpura; anti neutrophil cytoplasmic anti-body
    (ANCA) positivity (Myeloperoxidase or proteinease 3).
    3. History of relapsing (at least 1 confirmed EGPA relapse within last 2
    years and > 12 weeks prior to screening, or refractory (failure to attain
    remission, defined as BVAS=0 and oral corticosteroid (OCS) dose <=7.5
    mg/day of prednisolone or equivalent, following standard induction
    regimen for at least 3 months and within 6 months prior to screening, or
    recurrence of symptoms upon OCS tapering at any dose of ≥7.5 mg/day
    prednisolone or equivalent.
    If induction with glucocorticoidsalone, patient must have failed to attain
    remission after 3 months and the glucocorticoid dose must be ≥15
    mg/day prednisolone or equivalent for the 4 weeks prior to
    randomization.
    4. Must be on a stable dose of oral prednisolone or prednisone of ≥7.5
    mg/day (but not >50mg/day) for at least 4 weeks prior to
    randomization.
    5. If receiving immunosuppressive therapy (excluding
    cyclophosphamide) the dose must be stable for the 4 weeks prior to
    randomization and during the study (dose reductions for safety reasons
    will be permitted).
    6. QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle
    branch block.
    7. Females of childbearing potential must use an acceptable method of
    birth control from signing the informed consent for at least 12 weeks after the
    last study drug administration.
    E.4Principal exclusion criteria
    1. Diagnosed with granulomatosis with polyangiitis (GPA) or
    microscopic polyangiitis (MPA)
    2. Organ or life-threatening EGPA < 3 months prior to screening
    3. Currently pregnant or breastfeeding, or planning to become pregnant
    during study participation.
    4. Current malignancy or history of malignancy, unless received
    curative therapy >5 years ago, or >1 year ago for basal cell carcinoma,
    localized squamous cell carcinoma of the skin or in situ carcinoma of the
    cervix
    5. An untreated or refractory helminth parasitic infection < 24 weeks
    prior to screening
    6. Unstable liver disease
    7. Severe or clinically significant, uncontrolled cardiovascular disease
    8. Other concurrent disease that may put the patient at risk, or may
    influence the results of the study, or the patients' ability to complete
    entire duration of the study
    9. Chronic or ongoing infectious disease requiring systemic antiinfective
    treatment
    10. Known immunodeficiency disorder or positive HIV test
    11. Prior receipt of mepolizumab, reslizumab, dupilumab or
    benralizumab. Receipt of intravenous/intramuscular/subcutaneous
    corticosteroids within 4 weeks prior to randomization, receipt of
    omalizumab within 130 days prior to screenin, rituximab within 6
    months prior to screening (or B-cells not recovered), interferon-α or
    alemtuzumab within 6 months prior to screening, receipt of anti-tumor
    necrosis factor therapy within 12 weeks prior to screening or an
    investigational non-biologic product within 30 days or 5 half-lives prior to screening, whichever is longer. Receipt of any other marketed or investigational biologic products within 4 months or 5 half-lives prior to screening, whichever is longer.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS=0 and OCS dose ≤ 4mg/day (Main Remission definition) at both weeks 36 and 48.
    Supportive endpoint: Proportion of patients who have achieved remission defined by BVAS =0 and OCS dose ≤ 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Both weeks 36&48
    E.5.2Secondary end point(s)
    Study secondary end point(s) – double-blind period:
    - Total accrued duration of remission for the following categories: 0 wk,
    >0 to <12 wk, 12 to <24 wk, 24 to <36 wk, ≥36 wk. Analysis will be
    repeated based on main and supportive remission definitions.
    - Time from randomisation to first EGPA relapse, where relapse is
    defined as any of the following:
    *Active vasculitis (BVAS >0); OR
    *Active asthma symptoms and/or signs with a corresponding worsening
    in ACQ-6 score; OR
    *Active nasal and/or sinus disease, with a corresponding worsening in
    at least one of the sino-nasal symptom questions warranting any of the
    following:
    an increase of OCS therapy (>4mg prednisolone total daily dose or
    equivalent);
    an increased dose or addition of an immunosuppressive agent;
    Hospitalisation related to EGPA worsening.
    - Proportion of patients in each category of average daily
    prednisolone/prednisone dose during weeks 48 to 52 using the following
    categories: 0; >0 to ≤4 mg; >4 to ≤7.5 mg and > 7.5 mg
    - Annualized relapse rate
    - Proportion of patients who have achieved remission within the first 24
    weeks and remained in remission for remainder of the double-blind
    treatment period. Analysis will be repeated based on main and
    supportive remission definitions.
    - BVAS, VDI, pulmonary function testing, asthma symptoms (ACQ-6), SNOT-22 questionnaire, health-related
    quality of life (SF-36v2), WPAI and blood eosinophil counts will be
    assessed as change from baseline over the 52-week treatment period. Descriptive statistics will be provided for PGIS and WPAI to assess change from baseline over the 52 week double-blind period.
    PGIC will be assessed as response proportions at each weekly
    assessment between Visits 2 and 4
    - Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and electrocardiogram (ECG).
    Study end point(s) for open label extension (OLE) period:
    - Remission, relapse (as defined in the secondary endpoints), OCS use
    -Safety and tolerability will be evaluated based on AEs, Vital signs,
    physical exam, Clinical laboratory, and ECG .
    -Serum benralizumab concentrations, Anti-benralizumab antibodies and
    neutralizing antibodies
    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 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.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) Yes
    E.8.2.2Placebo No
    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.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Belgium
    Canada
    France
    Germany
    Israel
    Italy
    Japan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days17
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 83
    F.4.2.2In the whole clinical trial 140
    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)
    Until the study is analysed it is not yet known the efficacy and safety of benralizumab in EGPA. Currently there are no arrangements for continued provision of the intervention for participants following the end of the open label extension.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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