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    Summary
    EudraCT Number:2018-003297-27
    Sponsor's Protocol Code Number:NLRC4/XIAP.2016.001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-03-28
    Trial results View 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 ConcernedGermany - BfArM
    A.2EudraCT number2018-003297-27
    A.3Full title of the trial
    Multicenter, double-blind, placebo-controlled, randomized withdrawal trial with Tadekinig alfa (r-hIL-18BP) in patients with IL-18 driven monogenic autoinflammatory conditions: NLRC4 mutation and XIAP deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Therapeutic use of Tadekinig alfa in NLRC4 mutation and XIAP deficiency
    A.4.1Sponsor's protocol code numberNLRC4/XIAP.2016.001
    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 SponsorAB2 Bio Ltd.
    B.1.3.4CountrySwitzerland
    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 supportAB2 Bio Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAB2 Bio Ltd.
    B.5.2Functional name of contact pointEduardo Schiffrin
    B.5.3 Address:
    B.5.3.1Street AddressInnovation Park Building B
    B.5.3.2Town/ cityLausanne
    B.5.3.3Post code1015
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041216940043
    B.5.6E-mailEduardo.Schiffrin@ab2bio.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/150/16
    D.3 Description of the IMP
    D.3.1Product nameTadekinig alfa
    D.3.2Product code r-hIL-18BP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    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 INNTadekinig alfa
    D.3.9.1CAS number 220712-29-8
    D.3.9.2Current sponsor coder-hIL-18BPa
    D.3.9.3Other descriptive nameTADEKINIG ALFA
    D.3.9.4EV Substance CodeSUB180338
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number85
    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
    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
    NLRC4 mutation
    XIAP deficiency
    E.1.1.1Medical condition in easily understood language
    NLRC4 mutation
    XIAP deficiency
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    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 clinical efficacy of Tadekinig alfa in monogenic autoinflammatory diseases with ongoing inflammation and deleterious mutations of NLRC4-MAS or XIAP
    - To assess laboratory/biological evidence of efficacy
    E.2.2Secondary objectives of the trial
    Secondary Efficacy Objective:
    - Main clinical features and laboratory biomarkers (characteristics of each patient profile) will be assessed longitudinally during the SAOL phase for each experimental subject
    Secondary Safety Objective:
    - To assess the safety and tolerability of Tadekinig alfa treatment in monogenic, autoinflammatory disease harboring deleterious mutations of NLRC4-MAS or XIAP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation). If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.) A genetic diagnosis from a local laboratory will be accepted for enrolment and start of treatment, to avoid any treatment delays for these severe conditions. However, the genetic diagnosis has to be confirmed by the central laboratory. If the genetic diagnosis is not confirmed, the patient will discontinue the study.
    - Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism. For these patients, genetic diagnosis at the central laboratory may show chimerism; thus, local genetic diagnosis prior to the bone marrow transplantation will be the main source to confirm the genetic diagnosis.
    - Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4
    - Patients receiving corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti rheumatic drugs (DMARDs), and/or IL-1 blockade with insufficient response to treatment upon enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed
    - Women of childbearing potential with negative urine pregnancy test (UPT) at all visits
    E.4Principal exclusion criteria
    - Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency
    - Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology)
    - Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy
    - Presence of life threatening infections
    - Oncologic causes of symptoms; current or previous history of malignancy
    - Presence of CNS manifestations
    - Patients suffering from familial hemophagocytic lymphohistiocytosis (f HLH)
    - Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods
    - Concomitant use of immunosuppression therapies excluded by the protocol.
    - Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
    - Hypersensitivity to the active substance or one of the excipients of the investigational product
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the time to first occurrence of disease reactivation (including full and partial disease reactivation) during the 16-week RW phase.
    E.5.1.1Timepoint(s) of evaluation of this end point
    16 weeks or occurence of first disease reactivation
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoint

    Response to therapy (including complete response and partial response) in the SAOL phase from Week 10 onwards and observed at least at 2 consecutive visits at least 2 weeks apart during the SAOL phase

    Other Secondary Efficacy Endpoints

    - Best response to therapy during the SAOL phase (including complete response and partial response and disease improvement)
    - Duration of response to therapy (including complete response and partial response) during the SAOL phase
    - Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase)
    - Treatment failures (i.e. patients who experience at least one disease reactivation)
    - Intensity of disease reactivations (defined by the level of activity given by the mAIDAI – both objective and subjective criteria)
    - Serum CRP, Serum Ferritin
    - Improvement of fevers, improvement of hepato/splenomegaly (clinical assessments if present at Baseline)
    - Improvement in serum albumin and liver transaminases, anemia and/or platelet count (if present at Baseline)
    - Hospital length of stay
    - Length of hospitalisation
    - Physician Global Assessment
    - Patient’s or caregiver’s qualitative evaluation of health status
    - Presence of skin rash - evolution if present at Baseline or appearance during the study
    - Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline
    - Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline

    Safety and Tolerability Endpoints

    - Adverse events will be reported
    - Physical examination findings and vital signs: clinically significant changes from Baseline
    - Laboratory assessments including clinically significant changes from Baseline in hematology with platelet counts, CRP, ESR, ferritin, fibrinogen, D-dimer, liver enzymes, creatinine and glomerular filtration rate. (All clinically significant abnormal laboratory results or assessments must be followed until they resolve (return to normal or Baseline values) or stabilize, or until they are judged by the Investigator to be no longer clinically significant)
    - Immunogenicity evaluation: Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
    - Local tolerability at the injection site
    E.5.2.1Timepoint(s) of evaluation of this end point
    34 weeks
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Genetic testing at screening : analysis to detect known detrimental gene mutations
    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 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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    Canada
    United States
    Germany
    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 the entire trial will be defined as the date of the final clinical database lock
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 13
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 4
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    in this case, the Informed consent will be signed by the legal guardian
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2
    F.4.2.2In the whole clinical trial 15
    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)
    At the completion of treatment, all participants will be offered to enter the Open-Label Extension study (OLE-NLRC4/XIAP.2016.001) if OLE eligibility criteria are fulfilled
    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 Decision2019-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-10-31
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