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    Summary
    EudraCT Number:2022-002314-17
    Sponsor's Protocol Code Number:JR-441-101
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2023-01-19
    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 ConcernedGermany - PEI
    A.2EudraCT number2022-002314-17
    A.3Full title of the trial
    Phase I/II study of weekly infusions of JR-441 in patients with mucopolysaccharidosis type IIIA
    Eine Studie der Phase I/II zu wöchentlichen Infusionen von JR-441 bei Patienten mit Mukopolysaccharidose Typ IIIA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I/II study of weekly infusions of JR-441 in patients with mucopolysaccharidosis type IIIA
    A.4.1Sponsor's protocol code numberJR-441-101
    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 SponsorJCR Pharmaceuticals Co., Ltd.
    B.1.3.4CountryJapan
    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 supportJCR Pharmaceuticals Co., Ltd.
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJCR Pharmaceuticals Co., Ltd.
    B.5.2Functional name of contact pointDevelopment Division
    B.5.3 Address:
    B.5.3.1Street Address3-19 Kasuga-cho
    B.5.3.2Town/ cityAshiya
    B.5.3.3Post code659-0021
    B.5.3.4CountryJapan
    B.5.6E-mailclinical_development@jp.jcrpharm.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 numberEU/3/21/2560
    D.3 Description of the IMP
    D.3.1Product nameJR-441
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available yet
    D.3.9.2Current sponsor codeJR-441
    D.3.9.3Other descriptive nameHuman N-sulfoglucosamine sulfohydrolase fused to a humanised monoclonal antibody targeting human transferrin receptor
    D.3.9.4EV Substance CodeSUB235366
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mucopolysaccharidosis type IIIA (MPS IIIA)
    MPS III is an autosomal recessive disease characterized by the accumulation of HS in the tissues throughout the body due to a deficiency in enzymes involved in glycosaminoglycan (GAG) degradation in lysosomes. In MPSIII type A the deficient enzyme is SGSH. MPS IIIA has an estimated birth prevalence of between 0.26 and 1.89 per 100,000 live births and manifests as a severe neurodegenerative disease with progressive developmental regression.
    E.1.1.1Medical condition in easily understood language
    MPS IIIA is a condition that affects the brain. It can negatively impact how a person thinks and behaves. It can lead to difficulties with walking and sleeping, chest and ear infections
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10056890
    E.1.2Term Mucopolysaccharidosis III
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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 safety and tolerability of repeated infusions of JR-441 in patients with MPS IIIA
    E.2.2Secondary objectives of the trial
    To characterize the pharmacokinetic (PKs) properties of JR-441, and evaluate the efficacy of JR-441 on pharmacodynamic (PD) biomarkers and on CNS symptoms in patients with MPS IIIA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    (1) Chronological age of ≥1 year and ≤18 years at time of signing ICF.
    (2) A subject who voluntarily signs an IRB or IEC-approved written ICF. If the subject is aged ≥1 year to ≤18 years at the time of informed consent, or willingness to participate in the study cannot be confirmed due to MPS IIIA-related intellectual disability, the subject’s legally acceptable representative (e.g., his/her parents or guardians) may sign the ICF on behalf of the subject. Written informed assent must be obtained from the subject, wherever possible.
    (3) A subject with a confirmed diagnosis of MPS IIIA, based on all the following criteria:
    - Activity of the N-sulphoglucosamine sulphohydrolase (SGSH) enzyme below 10% of the lower reference level in white blood cells or cultured skin fibroblasts.
    - A normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes.
    - Presence of a pathological mutation in each of the individual alleles of the SGSH gene.
    Note: if SGSH enzyme activity results are abnormal (i.e., below the normal range of the assay) but still above the threshold of 10% of the lower reference level, MPS IIIA diagnosis may be confirmed based on family history and genotype following discussion and approval from the sponsor’s Medical Monitor.
    (4) Study subjects should have a minimal body weight of 10 kg.
    (5) Female subjects of childbearing potential or subjects whose female partner is of child-bearing potential agree to use a medically accepted, highly effective method of contraception as described in Section 10.5, from the time of signing the ICF. The method of contraception must be used during the study until 90 days for male subjects, and 30 days for female subjects after the final study drug administration or vasectomy at least 13 weeks prior to signing ICF.
    (6) For subjects with hearing impairment requiring hearing aid(s), every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurodevelopmental assessments, and parent/legally acceptable representative or subject agrees to encourage wearing them during the study and on neurodevelopmental function test days.
    (7) Medically stable and able to accommodate the protocol requirements, including travel without placing an undue burden on the patient/patient’s family, as determined by the principal investigator.
    E.4Principal exclusion criteria
    (1) A subject who has received gene therapy treatment or hematopoietic stem cell transplantation (HSCT) with successful engraftment.
    (2) A subject who is pregnant or breast feeding.
    (3) A subject who has received another investigational drug or product within 4 months or 5 half-lives (whichever is longer) before the time of providing informed consent.
    (4) A subject who is participating concurrently or who has participated prior (within 30 days of enrolment into this study) in a study involving invasive procedures.
    (5) A subject who has received Genistein within 4 months before the time of providing informed consent.
    (6) A subject who has received KINERET® (anakinra) within 4 months before the time of providing informed consent.
    (7) A subject who has developed serious drug allergy or hypersensitivity to any components of JR-441 or medications likely prescribed during the study, which, in the opinion of the principal investigator or sub-investigator, would be an impediment towards completion of the study.
    (8) A subject unable to undergo lumbar puncture.
    (9) A subject unable to undergo MRI.
    (10) A subject who has had a ventriculoperitoneal (VP) shunt placed or any other brain surgery or has a clinically significant VP shunt malfunction within 30 days of screening (Subjects may be rescreened after the 30-day waiting period has elapsed).
    (11) A subject has a history of bleeding disorder or current use of medications that, in the opinion of the investigator, place them at risk of bleeding following lumbar puncture.
    (12) A subject who has a history of poorly controlled seizures.
    (13) Serology consistent with human immunodeficiency virus (HIV) exposure or consistent with active hepatitis B (HepB) or C (HepC) infection.
    (14) A subject who has lab abnormalities with CTCAE grade ≥ II for liver function test, bilirubin, creatinine, hemoglobin, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time (aPTT), except subject whose bilirubin elevated due to Gilbert’s Syndrome.
    (15) A subject with known iron-metabolism disorder.
    (16) A subject with visual or hearing impairment sufficient, in the clinical judgment of the principal investigator or sub-investigator, to preclude cooperation with neurodevelopmental testing.
    (17) A subject currently receiving psychotropic or other medications which in the principal investigator’s or sub-investigator’s opinion, would be likely to substantially confound test results.
    (18) A subject who has a medical condition or extenuating circumstance that, in the opinion of the principal investigator or sub-investigator, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data.
    (19) A subject who is ineligible to participate in the study in the opinion of the principal investigator or sub-investigator.
    E.5 End points
    E.5.1Primary end point(s)
    1) Occurrence of adverse events (AEs)
    2) Changes in safety laboratory tests (hematology, coagulation, blood biochemistry, iron-related tests, and urinalysis)
    3) Changes in vital signs (pulse rate, body temperature, blood pressure, respiratory rate, and percutaneous oxygen saturation)
    4) Changes in 12-lead electrocardiogram (ECG)
    5) Number and severity of infusion-associated reactions (IARs), occurrence of anaphylaxis
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) AEs: from the time of providing written informed consent until the day of the last observation (Visit 261) or 30 days after discontinuation visit
    2) Changes in laboratory tests: Screening, before Administration, every week up to V4, V7, V14, V27, V40, V53, V66, V79, V92, V105, V118, V131, V144, V157, V170, V183, V196, V209, V222, V235, V248, V261 Discontinuation. Additional assessmentes possible as per investigator's judgement.
    3) Changes in vital signs: Screening, before Administration, every week from V2 to V52, V53, every week from V59 to V261 Discontinuation.
    4) Changes in 12-lead ECG: Screening, V27, V53, V105, V157, V209, V261, Discontinuation.
    5)Number and severity of infusion-associated reactions (IARs), occurrence of anaphylaxis: from Screening to V261 or Discontinuation
    E.5.2Secondary end point(s)
    -Plasma drug concentration*
    -Plasma PK parameters *
    * Endpoints applicable to the first 12 subjects enrolled
    Changes in the following parameters from baseline to each evaluation time point:
    -Heparan sulfate (HS) concentration in cerebrospinal fluid (CSF) and serum, and HS concentration relative to creatinine concentration in urine
    -Cognitive function assessed by Cognitive scale [Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)] and/or Nonverbal Index (NVI) [Kaufman Assessment Battery for Children, Second Edition (KABC-II)]
    -Adaptive behavior assessment [Vineland Adaptive Behavior Scale, Second Edition (VABS-II), Aberrant Behavior Checklist, Second Edition (ABC-II) and Sanfilippo Behavior Rating Scale (SBRS)]
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to V261/Discontinuation

    The formal statistical analyses of the completed Visit 59 data will be performed after the last subject in this study achieves the Visit 59 assessment. The final analysis of the completed Visit 261 data will be performed after all the subjects completed the assessment at Visit 261.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 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 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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 22
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 21
    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) No
    F.1.2.1Number of subjects for this age range: 0
    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
    Patients (children and adults), who might be mentally handicapped due to MPS IIIA-related intellectual disability, will be enrolled in the trial. In such cases the legally acceptable representative will consent on the patient's behalf.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    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
    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 Decision2023-07-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-04-28
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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