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    Summary
    EudraCT Number:2017-003083-13
    Sponsor's Protocol Code Number:250-202
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-11-27
    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 number2017-003083-13
    A.3Full title of the trial
    A Multicenter, Multinational, Extension Study to Evaluate the Long-Term Safety and Efficacy of Intracerebroventricular BMN 250 in Patients with Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)
    Estudio de extensión multicéntrico, internacional, para evaluar la seguridad y la eficacia a largo plazo de BMN 250 intracerebroventricular en pacientes con mucopolisacaridosis tipo IIIB (MPS IIIB, síndrome de Sanfilippo tipo B)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 study to evaluate Long-Term Safety and Efficacy of BMN 250 in Patients with MPS Type IIIB
    Estudio fase 2 para evaluar la seguridad y la eficacia a largo plazo de BMN 250 en pacientes con MPS tipo IIIB
    A.4.1Sponsor's protocol code number250-202
    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 SponsorBioMarin Pharmaceutical Inc.
    B.1.3.4CountryUnited States
    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 supportBiomarin Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin Pharmaceutical Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address105 Digital Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.6E-mailClinicaltrials@bmrn.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/213/14
    D.3 Description of the IMP
    D.3.1Product nameN/A
    D.3.2Product code BMN 250
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraventricular use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.2Current sponsor codeBMN 250
    D.3.9.3Other descriptive nameRHNAGLU-IGF2
    D.3.9.4EV Substance CodeSUB177868
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 IIIB (Sanfilippo Syndrome Type B, MPS
    IIIB)
    Mucopolisacaridosis tipo IIIB (MPS IIIB, síndrome de Sanfilippo tipo B)
    E.1.1.1Medical condition in easily understood language
    NAGLU deficiency
    NAGLU deficiencia
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10056918
    E.1.2Term Sanfilippo's syndrome
    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
    •Evaluate the long-term safety and tolerability of BMN 250
    administered to subjects with MPS IIIB by an implanted ICV reservoir
    and catheter
    • Evaluate the impact of long-term BMN 250 treatment on cognitive
    function in patients with MPS IIIB as assessed by development
    quotient (DQ)
    - Evaluar la seguridad y tolerabilidad del tratamiento a largo plazo con BMN 250 administrado a pacientes con MPS IIIB mediante un depósito implantado y una sonda ICV.
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la función cognitiva de pacientes con MPS IIIB, evaluado por el coeficiente de desarrollo (DQ).
    E.2.2Secondary objectives of the trial
    • Evaluate the impact of long-term BMN 250 treatment on cognitive
    function in patients with MPS IIIB as assessed by age equivalent
    score (AEq)
    • Characterize immunogenicity of long-term BMN 250 treatment in
    CSF and serum
    • Evaluate the impact of long-term BMN 250 treatment on CSF,
    serum and urine GAGs
    • Evaluate the impact of long-term BMN 250 treatment on brain
    structure assessed by magnetic resonance imaging (MRI)
    • Evaluate the impact of long-term BMN 250 treatment on adaptive
    function derived from the Vineland Adaptive Behavior Scales, 2nd
    edition (VABS-II)
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la función cognitiva de pacientes con MPS IIIB, evaluado por la puntuación de edad equivalente (EEq).
    - Caracterizar la inmunogenia del tratamiento a largo plazo con BMN 250 en el LCR y el suero.
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 en los GAG en el LCR, suero y orina.
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la estructura cerebral, evaluado por resonancia magnética (RM).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Must have completed 48 weeks in Part 2 of Study 250-201 and enter
    250-202 within 8 weeks of study completion
    • Written informed consent from parent or legal guardian and assent
    from subject, if required
    • Has the ability to comply with protocol requirements, in the opinion
    of the investigator
    • Males and females who are of reproductive age should practice true
    abstinence, defined as no sexual activity, during the study and for 6
    months after the study has been completed (or withdrawal from
    the study). If sexually active and not practicing true abstinence,
    males and females of reproductive age must use a highly effective
    method of contraception while participating in the study.
    • If female with childbearing potential, must have a negative
    pregnancy test at the Screening visit and be willing to have
    additional pregnancy tests during the study.
    - Haber terminado las 48 semanas en la parte 2 del estudio 250-201 y participar en el 250-202 en las 8 semanas antes de finalizar el estudio.
    - Consentimiento informado por escrito de los padres o del tutor legal y asentimiento del paciente, si se requiere.
    - Ser capaz de cumplir los requisitos del protocolo, según el criterio del investigador.
    - Los pacientes de ambos sexos en edad fértil practicarán la abstinencia real, definida como ausencia de actividad sexual, durante el estudio y 6 meses después de finalizar el estudio (o abandonar el mismo). Si son sexualmente activos y no practican la abstinencia real, los varones y las mujeres en edad fértil utilizarán un método anticonceptivo eficaz durante su participación en el estudio.
    - Las mujeres en edad fértil deben obtener un resultado negativo en la prueba de embarazo en la visita de selección y estar dispuestas a someterse a otras pruebas de embarazo durante el estudio.
    E.4Principal exclusion criteria
    Individuals who meet any of the following exclusion criteria are ineligible to participate in this study:
    • Has both a DQ score < 20 and DQ score < 25% that of the 250-201
    Baseline DQ score at the 250-201 Week 48 visit
    • Would not benefit from enrolling in the study in the opinion of the
    investigator
    • Has received stem cell, gene therapy or ERT (other than BMN 250)
    for MPS IIIB
    • Has contraindications for neurosurgery (eg, congenital heart
    disease, severe respiratory impairment, or clotting abnormalities)
    • Has contraindications for MRI scans (eg, cardiac pacemaker, metal
    fragment or chip in the eye, or aneurysm clip in the brain)
    • Has a history of poorly controlled seizure disorder
    • Is prone to complications from intraventricular drug administration,
    including patients with hydrocephalus or ventricular shunts
    • Has received any investigational medication other than BMN 250
    within 30 days prior to the Baseline visit or is scheduled to receive
    any investigational drug during the course of the study
    • Has a medical condition or extenuating circumstance that, in the
    opinion of the 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.
    • Is pregnant at any time during the study
    - Tener una puntuación DQ < 20 y una puntuación DQ < 25 % de la puntuación DQ inicial en el estudio 250-201 en la visita de la semana 48 del estudio 250-201.
    - No beneficiarse de su inclusión en el estudio, a criterio del investigador.
    - Haber recibido células madre, tratamiento génico o TES (distinta de BMN 250) para la MPS IIIB.
    - Tener contraindicaciones para la neurocirugía (p. ej., cardiopatía congénita, trastorno respiratorio grave o alteraciones de la coagulación).
    - Tener contraindicaciones para las exploraciones por RM (p. ej., marcapasos cardíaco, fragmentos metálicos o un chip ocular o un clip para aneurisma en el cerebro).
    - Tener antecedentes de trastornos convulsivos mal controlados.
    - Propensión a tener complicaciones por la administración intraventricular de medicamentos, incluidos pacientes con hidrocefalia o derivaciones ventriculares.
    - Haber recibido algún medicamento en fase de investigación, distinto a BMN 250, en los 30 días anteriores a la visita inicial o tener programada la administración de algún medicamento en fase de investigación durante el transcurso del estudio.
    - Padecer una enfermedad o circunstancias especiales que, a criterio del investigador, podrían afectar a la capacidad del paciente para cumplir los requisitos del protocolo, el bienestar o la seguridad del paciente o la interpretación de los datos clínicos del paciente.
    - Estar embarazada en cualquier momento del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate the lon-term safety and tolerability of BMN 250 administered to
    subjects with MPS IIIB by an implanted intracerebroventricular (ICV)
    reservoir and catheter.

    To evaluate the lon-term impact of BMN 250 treatment on cognitive function in patients with MPS IIIB as assessed by developmental quotient (DQ).
    Evaluar la seguridad y tolerabilidad del tratamiento a largo plazo con BMN 250 administrado a pacientes con MPS IIIB mediante un depósito implantado y una sonda ICV.

    Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la función cognitiva de pacientes con MPS IIIB, evaluado por el coeficiente de desarrollo (DQ).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The safety evaluation will include continuous monitoring of AEs and concomitant medications. Clinical laboratory assessments will be performed at Baseline and every 4 weeks for the first 96 weeks, then Q12W thereafter. CSF for cell count, protein, and glucose will be collected prior to each weekly infusion. A complete physical examination will be performed at Baseline and every 24 weeks thereafter. The exam includes an assessment of general appearance, vital signs, measurements of height, weight and head circumference, a detailed neurological examination, and an assessment of cardiovascular, respiratory, and gastrointestinal systems. Brief physical exams are performed at weekly dosing visits when complete exams are not performed. ECG and EEG will be performed at the end of the study
    La evaluación de seguridad incluirá supervisión continua de AA y medicación concomitante. Los análisis clínicos se realizarán en visita inicial y cada 4 semanas durante las primeras 96S, posteriormente cada 12S. El LCR para recuento celular, determinación de proteínas y glucosa se obtendrá antes de cada infusión semanal. Se realizará exploración física completa en visita inicial y posteriormente, cada 24S. ésta incluye evaluación del aspecto general, constantes vitales, mediciones de estatura, peso y perímetro craneal, exploración neurológica detallada y evaluación de aparatos cardiovascular, respiratorio y digestivo. Cuando no se realicen exploraciones completas, se realizarán breves exploraciones físicas en visitas de administración semanales. Se realizará ECG y EEG al final del estudio.
    E.5.2Secondary end point(s)
    The secondary objectives of this study are:
    *to evaluate the long-term impact of BMN 250 treatment on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq)
    *to characterize single- and repeated-dose pharmacokinetics (PK) of
    BMN 250 in cerebrospinal fluid (CSF) and plasma
    *to characterize immunogenicity of long-term BMN 250 treatment in CSF and serum
    *to evaluate the impact of BMN 250 treatment on CSF, serum and urine GAGs
    *to evaluate the impact of BMN 250 treatment on brain structure
    assessed by magnetic resonance imaging (MRI)
    *To evaluate the impact of BMN 250 treatment on adaptive function
    derived from the Vineland Adaptive Behavior Scales, 2nd edition (VABSII).
    Los objetivos secundarios de este estudio son:
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la función cognitiva de pacientes con MPS IIIB, evaluado por la puntuación de edad equivalente (EEq).
    - Caracterizar la inmunogenia del tratamiento a largo plazo con BMN 250 en el LCR y el suero.
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 en los GAG en el LCR, suero y orina.
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la estructura cerebral, evaluado por resonancia magnética (RM).
    - Evaluar el impacto del tratamiento a largo plazo con BMN 250 sobre la función adaptativa derivada de las Escalas de conducta adaptativa de Vineland, 2.ª edición (VABS-II).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The CSF, as well as blood collected at less frequent intervals, will be used for GAG analyses and/or exploratory analyses of the biochemical, molecular, cellular and genetic/genomic aspects of MPS IIIB.

    CSF and blood (serum) will be drawn throughout the study to analyze immunogenicity

    Urine will be collected for GAG and creatinine analyses as well as for exploratory analyses at Baseline and every 24 weeks thereafter.

    Brain structure will be evaluated by MRI during Baseline visits and at Weeks 24 and 48.
    El LCR, así como la sangre obtenida a intervalos menos frecuentes, se usará para los análisis de determinación de GAG y/o análisis exploratorios de los aspectos bioquímicos, moleculares, celulares y genéticos/genómicos de la MPS IIIB.

    Durante todo el estudio se obtendránLCR y sangre (plasma) para estudiar la inmunogenia
    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) 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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
    Baseline Control
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Baseline Control
    E.8.2.4Number of treatment arms in the trial1
    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 EEA3
    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
    Argentina
    Australia
    Colombia
    Germany
    Spain
    Taiwan
    Turkey
    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
    LVLS
    UVUP
    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 months6
    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 months6
    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: 33
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 28
    F.1.1.6Adolescents (12-17 years) No
    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 No
    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
    The subjects included in this trial are between 1 to 10 years of age.
    Therefore before any study-related procedures are performed, parents
    or legal guardians of the subjects must provide informed consent, and
    if required, subjects must assent.
    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 15
    F.4.2.2In the whole clinical trial 33
    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)
    Expected normal tratment for the condition
    Tratamiento normal esperado para la condición
    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 Decision2017-12-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-22
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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