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    Summary
    EudraCT Number:2014-001411-39
    Sponsor's Protocol Code Number:ABT-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-06-27
    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 ConcernedSpain - AEMPS
    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
    Ensayo Clínico de terapia génica fase I/II con rAAV9.CMV.NAGLU para la Mucopolisacaridosis tipo 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
    Ensayo Clínico de transferencia génica para la Mucopolisacaridosis tipo IIIB
    A.4.1Sponsor's protocol code numberABT-002
    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 Inc
    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 pointJuan
    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 rAAV9.CMV.hNAGLU
    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.
    MPS IIIB es una enfermedad de depósito lisosomal, causada por un defecto genético de la enzima α-N- acetilglucosaminidasa (NAGLU). Los niños parecen normales al nacer, pero la enfermedad es progresiva, con el deterioro de las habilidades sociales y de adaptación, la disminución neurocognitiva y la muerte prematura. La muerte se produce normalmente a finales de la segunda o principios de la tercera década. Es de destacar que no existe un tratamiento disponible actualmente para la enfermedad.
    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.
    La mucopolisacaridosis tipo IIIB es una enfermedad genética en niños, causada por la toxicidad de un acúmulo de sustancias en el organismo que generan un deterioro progresivo.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    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
    Determination of safety based on development of unacceptable toxicity
    Determinación de la seguridad basada en el desarrollo de toxicidad inaceptable
    E.2.2Secondary objectives of the trial
    1. Reduction of CSF, plasma or urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment
    2. Increase in CSF or plasma NAGLU enzyme activity levels at 6 and/or 12 months after treatment
    3. Reduced liver and/or spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI)
    4. Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months after treatment, as assessed by parent report using the Vineland Adaptive Behavior Scale II
    5. Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale (brief IQ), the Mullen Scales of Early Learning; and by parent report using the Sanfilippo Behavior Rating Scale
    1. Reducción del heparan sulfato o glicosaminoglicanos (GAG) en LCR, orina o plasma a los 6 y/o 12 meses después del tratamiento
    2. Aumento de los niveles de actividad enzimatica NAGLU en LCR o plasma a los 6 y/o 12 meses después del tratamiento
    3. Reducción de los volúmenes del hígado y/o del bazo a los 6 y/o a los 12 meses del tratamiento, determinado mediante RM
    4. Mejora de la adaptación funcional o detención de la disminución de la adaptación funcional a los 6 y/o 12 meses después del tratamiento, según la evaluación del informe de los padres utilizando la Escala Vineland de Conducta Adaptativa II
    5. Mejora de la capacidad cognitiva o detención del deterioro cognitivo a los 6 y/o a los 12 meses del tratamiento, según la valoración del examen directo del niño mediante la Escala Internacional de Rendimiento Leiter, las Escalas Mullen de Aprendizaje Temprano (CI abreviado) y mediante informe de los padres utilizando la escala de valoración conductual de Sanfilippo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 6 months old or greater
    2. Confirmed diagnosis of MPS IIIB by both of the following methods:
    a. No detectable or significantly reduced NAGLU enzyme activity by plasma, serum, or leukocyte assay.
    b. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
    3. Clinical history or examination features of neurologic dysfunction
    1. 6 meses de edad o más.
    2. Diagnóstico confirmado de MPSIIIB por los dos métodos:
    a. Sin actividad detectable o con actividad enzimática de NAGLU significativamente reducida en plasma, suero o mediante un ensayo en leucocitos
    b. Análisis genómico de la mutación del DNA que demuestre las mutaciones heterozigóticas compuestas u homozigóticas del gen NAGLU
    3. Historia clínica o signos de disfunción neurológica en la exploración
    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. Prior treatment with NAGLU enzyme replacement therapy (ERT)
    4. Has evidence of an attenuated phenotype of MPS IIIB, as judged by the principal investigator
    5. Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
    6. Inability to be safely sedated in the opinion of the clinical anesthesiologist
    7. Active viral infection based on clinical observations
    8. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
    9. Subjects with anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
    10. Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
    11. 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
    12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
    13. Uncontrolled seizure disorder, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on anticonvulsive medications may be included
    14. Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy
    15. Any other situation that would exclude the patient from undergoing any other procedure required in this study
    16. Subjects with cardiomyopathy or significant congenital heart abnormalities
    17. The presence of significant non-MPS IlIB related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
    18. 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
    19. Female participant who is pregnant or demonstrates a positive urine or hCG result at screening assessment (if applicable).
    1. Incapacidad para participar en la evaluación clínica, según criterio del investigador principal
    2. Identificación de dos variantes nulas o sin sentido en el test genético del gen NAGLU, según criterio del investigador principal
    3. Tratamiento previo de remplazo enzimático (TRE) con NAGLU
    4. Tener evidencia de un fenotipo atenuado de MPSIIIB, según criterio del investigador principal
    5. Presencia de una condición médica concomitante que impida la punción lumbar o el uso de anestesia
    6. Incapacidad para recibir una adecuada sedación según opinión del anestesista
    7. Infección viral activa basada en observaciones clínicas
    8. Enfermedad concomitante o necesidad de tratamiento médico crónico que según opinión del investigador principal (IP) cree riesgos innecesarios para la transferencia génica
    9. Demostración de títulos de anticuerpos totales anti-AAV9 ≥ 1:100 mediante inmunoensayo tipo ELISA
    10. Serología acorde con exposición a VIH, o serología acorde con infección activa de hepatitis B o C
    11. Trastorno hemorrágico o cualquier otra afección médica o circunstancia en la que esté contraindicada una punción lumbar (para la obtención de líquido cefalorraquídeo (LCR) conforme a la política institucional del centro
    12. Deterioro visual o auditivo suficiente para impedir, la cooperación con las pruebas de neurodesarrollo
    13. Enfermedad con crisis convulsivas sin estabilizar, debido a la necesidad de múltiples exploraciones con resonancia magnética (RM) como parte del protocolo del estudio. Los sujetos que se encuentren estables con medicación anticonvulsiva podrán ser incluidos
    14. Cualquier elemento (elementos de ortodoncia, etc.) que impida al paciente de poder someterse a una RM según la política institucional del centro
    15. Cualquier otra situación que impida al paciente de someterse a cualquier otro procedimiento necesario para este estudio.
    16. Sujetos con cardiomiopatía o cardiopatías congénitas importantes
    17. La presencia de deterioro importante del sistema nervioso central (SNC) no relacionado con MPS IIIB o alteraciones de la conducta que confundan el rigor científico o la interpretación de los resultados del estudio
    18. Valores analíticos alterados de grado 2 o mayores según se define en CTCAEv4.0, para GGT, bilirrubina total, creatinina, hemoglobina, recuento de glóbulos blancos, recuento de plaquetas, tiempo de protrombina y tiempo de tromboplastina parcial activado
    19. Participante femenina que está embarazada o muestre β-HCG positivo en suero en la prueba de evaluación
    E.5 End points
    E.5.1Primary end point(s)
    Determination of safety: Adverse events and Serious Adverse events
    Determinación de la seguridad: Acontecimientos Adversos y acontecimientos adversos graves
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse events will be evaluated along the entire trial during 24 months
    Los eventos adversos serán evaluados a lo largo de todo el ensayo clínico por un total de 24 meses.
    E.5.2Secondary end point(s)
    1. Reduction of CSF, plasma or urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment
    2. Increase in CSF or plasma NAGLU enzyme activity levels at 6 and/or 12 months after treatment
    3. Reduced liver and/or spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI)
    4. Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months after treatmnt, as assessed by parent report using appropiate scale.
    5. Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child and by parent report using the appropiate scales.
    1. Reducción del heparan sulfato o glicosaminoglicanos (GAG) en LCR, orina o plasma a los 6 y/o 12 meses después del tratamiento
    2. Aumento de los niveles de actividad enzimatica NAGLU en LCR o plasma a los 6 y/o 12 meses después del tratamiento
    3. Reducción de los volúmenes del hígado y/o del bazo a los 6 y/o a los 12 meses del tratamiento, determinado mediante RM
    4. Mejora de la adaptación funcional o detención de la disminución de la adaptación funcional a los 6 y/o 12 meses después del tratamiento, según la evaluación del informe de los padres utilizando la escala adecuada.
    5. Mejora de la capacidad cognitiva o detención del deterioro cognitivo a los 6 y/o a los 12 meses del tratamiento, según la valoración del examen directo del niño e informe de los padres mediante las escalas adecuadas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Day -45 to -1 (patient inclusion); day 1, 7, 14, 30, 60, 90, 180, month 12, month 18, month 24
    - Day -45 to -1 (patient inclusion); day 7, 14, 30, 60, 90, 180, month 12, month 18, month 24
    - Day -45 to -1 (patient inclusion); days 30, 180, month 12, month 24
    - Day -45 to -1: day 180, month 12, month 18, month 24
    - Day -45 to -1: day 180, month 12, month 18, month 24
    - Día -45 a -1 (inclusión paciente); días 7, 14, 30, 60, 90, 180, 12 meses, 18 meses, 24 meses
    -Día -45 a -1 (inclusión paciente); días 7, 14, 30, 60, 90, 180, 12 meses, 18 meses, 24 meses
    - Día -45 a -1 (inclusión paciente); días 30, 180, mes 12, mes 24
    - Día -45 a -1: 180 días, mes 12, mes 18, mes 24
    - Día -45 a -1: 180 días, mes 12, mes 18, mes 24
    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
    Escalada de dosis
    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 EEA8
    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
    Ultima visita del ultimo paciente
    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: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    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 prepared.
    Estos niños tienen problemas cognitivos severos que dificultan su entendimiento de una explicación del estudio y firma del consentimiento informado.Basado en una opinión experta, se ha preparado unn único ICF para los padres o representantes legales.
    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 5
    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)
    Following the active two-year follow-up phase of the study, subjects will then be asked to continue with annual visits with their standard care physician for a total of 5 years long term monitoring. When feasible, subjects will be asked to continue to be followed at the Clinical Sites participanting in this clinical trial. The site staff is responsible for detecting, documenting and reporting SAEs in this annual follow up performed under common clinical practiques.
    Después de la fase activa de seguimiento de dos años del estudio, se les pedirá a los sujetos continuar las visitas anuales con su médico habitual por 5 años de seguimiento a largo plazo. Cuando sea posible, se pedirá a los sujetos que continúen su seguimiento en los hospitales clínicos participantes en este ensayo clínico. El personal del hospital se encarga de detectar, documentar e informar en este seguimiento anual sobre reacciones adversas graves, bajo su práctica clínica habitual.
    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 Decision2018-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-01
    P. End of Trial
    P.End of Trial StatusOngoing
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