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    Summary
    EudraCT Number:2014-001411-39
    Sponsor's Protocol Code Number:ABT-002
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-10-29
    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 number2014-001411-39
    A.3Full title of the trial
    Phase I/II gene transfer clinical trial of rAAV9.CMV.hNAGLU for Mucopolysaccharidosis (MPS) IIIB
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene transfer clinical trial for Mucopolysaccharidosis IIIB
    A.4.1Sponsor's protocol code numberABT-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03315182
    A.5.4Other Identifiers
    Name:Program nameNumber:ABO-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 SponsorAbeona Therapeutics Europe SL.
    B.1.3.4CountrySpain
    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 supportAbeona Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbeona Therapeutics Inc
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street AddressAvenida de Manoteras 30, A207-208
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28050
    B.5.3.4CountrySpain
    B.5.4Telephone number+34911726254
    B.5.5Fax number+34911726254
    B.5.6E-mailabeonaeu@abeonatherapeutics.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/3/16/1825
    D.3 Description of the IMP
    D.3.1Product namerAAV9.CMV.hNAGLU
    D.3.2Product code ABO-101
    D.3.4Pharmaceutical form Solution for infusion
    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 INNrAAV9.CMV.hNAGLU
    D.3.9.2Current sponsor coderAAV9.CMV.hNAGLU
    D.3.9.3Other descriptive namerAAV9.CMV.hNAGLU
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50000000000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    MPS IIIB is a devastating lysosomal storage disease, caused by a N-α-acetylglucosaminidase (NAGLU) gene defect. Infants with MPS IIIB appear normal at birth, but the disease is relentlessly progressive, with deterioration of social and adaptive abilities, neurocognitive decline, and premature death. Death typically occurs by end of the second or beginning of the third decade. Quite importantly, there is no treatment currently available for the disease.
    E.1.1.1Medical condition in easily understood language
    Mucopolysaccharidosis type IIIB is a genetic disease in children, caused by the toxicity of an accumulation of substances in the body that generate a progressive deterioration.
    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
    • Change from baseline in Age Equivalent Development score compared
    with Natural History Study
    • Safety
    E.2.2Secondary objectives of the trial
    • Change from baseline of CSF heparan sulfate, plasma or urine glycosaminoglycans or heparan sulfate, CSF or plasma NAGLU enzyme activity levels after treatment
    • Change from baseline in liver and/or spleen volumes after treatment
    • Change from baseline in brain volumes after treatment
    • Change from baseline in Cognitive Age Equivalent compared to Natural History Study
    • Change from baseline in Adaptive Age Equivalent score, Developmental Quotient after treatment compared to Natural History Study
    • Change from baseline in the Sanfilippo Behaviour Rating Scale, Pediatric Quality of Life Inventory, parent quality of life
    • Determination of vector shedding analysis in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment (ERA)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of MPS IIIB confirmed by the following methods:
    a. No detectable or significantly reduced NAGLU enzyme activity by plasma assay, and
    b. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
    2. Age 6 months to 2 years or children older than 2 years with a minimum cognitive Development Quotient (DQ) of 60 or above (calculated by Bayley Scales of Infant and Toddler Development - Third Edition and accepting values within the 95% Confidence Interval of the Cognitive Developmental Age Equivalents)
    E.4Principal exclusion criteria
    1. Inability to participate in the clinical evaluation as determined by Principal Investigator.
    2. Identification of two nonsense or null variants on genetic testing of the NAGLU gene, as judged by the principal investigator
    3. Has evidence of an attenuated phenotype of MPS IIIB.
    4. Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics.
    5. Active viral infection based on clinical observations as infections by Adenoviruses, Epstein-Barr Virus, Cytomegalovirus, Respiratory Syncytial Virus.
    6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or precludes the child from participating in the protocol assessments and follow up, as autoimmune diseases requiring immunosuppression, such as juvenile rheumatoid arthritis or idiopathic thrombocytopenia purpura.
    7. Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay.
    8. Subjects with a positive response for the ELISPOT for T-cell responses to AAV9.
    9. Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection.
    10. Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy.
    11. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing.
    12. Uncontrolled seizure disorder.
    13. Any item (braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy.
    14. Any other situation that precludes the subject from undergoing procedures required in this study.
    15. Subjects with cardiomyopathy or significant congenital heart abnormalities.
    16. The presence of significant non-MPS IIIB related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
    17. Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT.
    18. Female participant who is pregnant or demonstrates a positive urine or βhCG result at screening assessment (if applicable).
    19. Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone).
    20. Previous treatment by Haematopoietic Stem Cell transplantation.
    21. Prior participation in a gene/cell therapy or ERT clinical trial.
    E.5 End points
    E.5.1Primary end point(s)
    • Change from baseline in the Age Equivalent Developmental score (calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children Second Edition, based on developmental age) compared with Natural History Study data [Time Frame: Month 6, 12, 18, 24 ]
    • Product safety as defined by the incidence, type and severity of treatment-related adverse events and serious adverse events [Time frame: Month 1, 2, 3, 6, 12, 18, 24]
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Change from baseline in the Age Equivalent Developmental score [Time Frame: Month 6, 12, 18, 24 ]
    • Product safety as defined by the incidence, type and severity of treatment-related adverse events and serious adverse events [Time frame: Month 1, 2, 3, 6, 12, 18, 24]
    E.5.2Secondary end point(s)
    • Change from baseline of CSF heparan sulfate after treatment [Time frame: Month 1, 6, 12, 24]
    • Change from baseline of plasma or urine glycosaminoglycans or heparin sulfate after treatment [Time frame: Month 1, 6, 12, 18, 24]
    • Change from baseline in CSF or plasma NAGLU enzyme activity levels after treatment [Time frame: Month 1, 6, 12, 24]
    • Change from baseline in liver and/or spleen volumes after treatment, as measured by magnetic resonance imaging (MRI) [Time frame: Month 1, 6, 12, 24]
    • Change from baseline in brain volumes after treatment, as measured by magnetic resonance imaging (MRI) [Time frame: Month 1, 6, 12, 24]
    • Change from baseline in the Cognitive Age Equivalent (Developmental Age) compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development – Third edition or the Kaufman developmental age [ Time Frame: Month 6, 12, 18, 24]
    • Change from baseline in the Adaptive Age Equivalent score after treatment compared to Natural History Study data, as assessed by parent report using the Vineland Adaptive Behavior Scale II Survey form [Time frame: Month 6, 12, 18, 24]
    • Change from baseline Developmental Quotient after treatment compared to Natural History Study data assessed by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children. Second Edition, based on chronological and developmental age [Time frame: Month 6, 12, 18, 24]
    • Change from baseline in the Sanfilippo Behavior Rating Scale [Time Frame: Month 6, 12, 18, 24]
    • Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales total score [ Time Frame: Month 6, 12, 18, 24]
    • Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) short form [Time Frame: Month 12, 24]
    • Determination of vector shedding analysis in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment (ERA).

    Exploratory Outcomes:
    • Change from baseline by brain magnetic resonance imaging (MRI) using DTI technology, compared to changes observed in Natural History Study data [Time Frame: Month 1, 6, 12, 24]
    • Change from baseline in sleep pattern as measured by a modified Children's Sleep Habits Questionnaire (CSHQ) [Time Frame: Month 6, 12, 18, 24]
    • Change from baseline in plasma and CSF cytokines [Time Frame:Month 1, 6, 12, 18, 24]
    • Change from baseline in CSF Gangliosides [GM2-GM3] [Time frame: Month 1, 6, 12, 18, 24]
    • Change from baseline in audiometry evaluations assessed by tympanometry, otoacoustic emissions (OAE) and auditory brainstem response (ABR) [Time Frame: Month 6, 12, 24]
    • Determination of neutralizing antibodies titers against AAV9 as determined by an in vitro infectivity assay [Time frame: Month 6, 12, 24].
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Change from baseline of CSF heparan sulfate [Time frame: Month 1, 6, 12, 24]
    • Change from baseline of plasma or urine glycosaminoglycans or heparin sulfate [Time frame: Month 1, 6, 12, 18, 24]
    • Change from baseline in CSF or plasma NAGLU enzyme activity levels [Time frame: Month 1, 6, 12, 24]
    • Change from baseline in liver and/or spleen, and brain volumes [Time frame: Month 1, 6, 12, 24]
    • Change from baseline in the Cognitive Age Equivalent, Adaptive Age Equivalent, Developmental Quotient, Sanfilippo Behavior Rating Scale, PedsQL Generic Core Scales total score [Time Frame: Month 6, 12, 18, 24]
    • Change from baseline in parent quality of life [ Time Frame: Month 12, 24]
    • Vector Shedding: Month 1 and then monthly until two consecutive samples are negative
    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 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 Yes
    E.8.1.7.1Other trial design description
    Dose escalation
    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 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 Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    France
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 9
    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: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    These children have severe cognitive problems making them very difficult to understand an explanation about the study and also to sign the informed consent. Based on a expert opinion, unique ICF for parents or legal representatives is proposed.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7
    F.4.2.2In the whole clinical trial 9
    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)
    After the 24 month visit, subjects will be invited to participate in a long term follow up study consisting of annual monitoring for a period of five years. If they do not accept to participate the PI will collect medical records according to the guidelines provided in this protocol.
    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 Decision2019-06-24
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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