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    Summary
    EudraCT Number:2013-003400-39
    Sponsor's Protocol Code Number:NGLU-CL02
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2016-02-17
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-003400-39
    A.3Full title of the trial
    A Phase I/II Open Label Study in MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously
    Estudio abierto de fase I/II en sujetos con MPS IIIB para evaluar la seguridad, farmacocinética y farmacodinámica/eficacia de SBC-103 administrado por vía intravenosa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 open label study in MPS IIIB subjects to investigate the long-term safety and effect of SBC-103 given by IV infusion.
    Estudio abierto de fase I/II en sujetos con MPS IIIB para evaluar la seguridad a largo plazo y el efecto de SBC-103 administrado por vía intravenosa.
    A.4.1Sponsor's protocol code numberNGLU-CL02
    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 SponsorAlexion Pharmaceuticals, 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 supportAlexion Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlexion Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointLoralie Brennan, Assoc Dir Clin Ops
    B.5.3 Address:
    B.5.3.1Street Address33 Hayden Ave.
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900 834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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/3/13/1144
    D.3 Description of the IMP
    D.3.1Product nameRecombinant Human Alpha-N-Acetylglucosaminidase (rhNAGLU)
    D.3.2Product code SBC-103
    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 INNnot available
    D.3.9.1CAS number 37288-40-7
    D.3.9.2Current sponsor codeSBC-103
    D.3.9.3Other descriptive namerhNAGLU
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 III, type B (MPS IIIB), Sanfilippo B
    Mucopolisacaridosis III, tipo B (MPS IIIB), Sanfilippo B
    E.1.1.1Medical condition in easily understood language
    Sanfilippo B
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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 the IV administration of SBC-103 in subjects with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) with evaluable signs or symptoms of developmental delay.
    Evaluar la seguridad y tolerabilidad de la administración intravenosa (IV) de SBC-103 en sujetos con mucopolisacaridosis III, tipo B (MPS IIIB, Sanfilippo B) con signos o síntomas evaluables de retraso del desarrollo .
    E.2.2Secondary objectives of the trial
    ? To characterize the PK profile of SBC-103 administered IV.
    ? To determine the effects of SBC-103 administered IV on the levels, onset and magnitude of changes in total HS in CSF, serum, and urine.
    ? To evaluate the PD/efficacy of doses of SBC-103 administered IV as measured by neurocognitive and developmental function and change in brain structures.
    ? To evaluate the impact of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability, and select PD/efficacy markers, including the reversibility of changes in levels of total HS in CSF, serum, and urine.
    - Determinar el perfil farmacocinético (FC) de SBC-103 administrado por vía IV.
    - Determinar los efectos de de SBC-103 por administración IV sobre el grado, la aparición y la magnitud de los cambios en la concentración de heparán sulfato (HS) total en líquido cefalorraquídeo (LCR), suero y orina.
    - Evaluar la farmacodinámica (FD)/eficacia de SBC-103 por administración IV determinada por la función neurocognitiva y del desarrollo y el cambio en las estructuras cerebrales.
    - Evaluar el impacto de la interrupción temporal del tratamiento con SBC-103 (entre las Partes A y B) sobre la seguridad, tolerabilidad y determinados marcadores de FD/eficacia, incluida la reversibilidad de las variaciones de la concentración total del HS en LCR, suero y orina.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A subject who meets all of the following inclusion criteria will be eligible to participate in this study:
    1. Has a definitive diagnosis of MPS IIIB, as determined by either of the following:
    a. Documented deficiency in NAGLU enzyme activity ?10% of the mean value in normal individuals (Heron, 2011, Am J Med Genet A) based on test results from a central laboratory at Screening.
    OR
    b. Documented functionally-relevant mutations in both alleles of the NAGLU gene based on historical test results from a local laboratory (if available) or results from the central laboratory at Screening.
    2. Greater than or equal to 2 years old and less than 12 years old at the time of written informed consent, and has an age equivalent of ?1 year on the Vineland II.
    3. Has documented developmental delay with onset before 6 years of age, as defined by:
    a. Cognitive delay evaluated by BSID-III or KABC-II.
    OR
    b. Language delay, plateauing or regression of language skills as determined by the Investigator and confirmed by the Vineland-II (communication domain) administered at Screening (eg, subject uses isolated words, associated words such as two-word combination, sentences, poor or reduced language and/or language difficult to understand).
    4. Subject or subject?s parent or legal guardian (if applicable) consents to participate in the study and provides informed consent prior to any study procedures being performed. If the subject is of minor age; he/she is willing to provide assent where required per local regulations, and if deemed able to do so.
    5. Female subjects who are of childbearing potential at the time of consent or who become of childbearing potential during participation on study (a) must have a negative urinepregnancy test at Screening, (b) cannot be breast feeding, and (c) must consent to use a highly reliable method of birth control (expected failure rate less than 5% per year) for the duration of the study and for 30 days after last dose of SBC-103. Women may be considered of non-childbearing potential if they have not started their menses or are surgically sterile (ie, total hysterectomy or bilateral salpingo-oophorectomy).
    6. Male subjects must consent to use a highly reliable method of birth control (expected failure rate less than 5% per year) during any sexual contact with females of childbearing potential while participating in the study and for 30 days following discontinuation from this study even if he has undergone a successful vasectomy.
    7. Willingness and ability to comply with protocol requirements to the extent that may be expected of a subject with cognitive impairment.

    Part B
    Qualifications for Participation in Part B (Therapy at 1 and/or 3 mg/kg)
    Subjects are eligible for continued SBC 103 dosing in Part B if they do not meet any Exclusion criteria and if they meet the following:
    1. Completion of Part A with no unmanageable study drug toxicity;
    2. Continue to meet Inclusion Criteria items 4-7; and
    3. SRC and Sponsor have reviewed the subject?s safety data from Part A and have deemed it acceptable for the subject to re-initiate dosing in Part B.

    Part C
    Qualifications for Participation in Part C (Therapy at 5 and/or 10 mg/kg)
    Subjects are eligible for continued SBC 103 dosing at a higher dose (5 or 10 mg/kg QOW) in Part C if they do not meet any Exclusion criteria and if they:
    1. Have completed at least 4 doses of 3 mg/kg in either Part A or Part B with no unmanageable study drug toxicity; and
    2. Continue to meet Inclusion Criteria items 4-7.
    Un sujeto que cumpla todos los criterios de inclusión siguientes será apto para participar en este estudio:
    1. Presenta un diagnóstico definitivo de MPS IIIB, determinado por lo siguiente:
    a. Deficiencia documentada en la actividad de la enzima alfa-N-acetilglucosaminidasa (NAGLU) <=10 % del valor medio en individuos normales (Heron, 2011, Am J Met Genet A) según los resultados de las pruebas de un laboratorio central en el periodo de selección.
    O BIEN
    b. Mutaciones documentadas relacionadas con la funcionalidad en ambos alelos del gen NAGLU según resultados de pruebas anteriores de un laboratorio local (si se encuentran disponibles) o resultados del laboratorio central en el periodo de selección.
    2. Niños de 2 o más años de edad y menores de 12 años de edad en el momento de firmar el consentimiento informado, y con un equivalente en edad de >=1 años en las Escalas de conducta adaptativa de Vineland, 2ª edición (Vineland-II).
    3. Presentar un retraso del desarrollo documentado con inicio antes de los 6 años de edad, definido por:
    a. Retraso cognitivo evaluado por BSID-III o KABC-II.
    O BIEN
    b. Retraso en el lenguaje, estancamiento o regresión de las capacidades lingüísticas según determine el investigador y lo confirme la escala Vineland-II (dominio de la comunicación) administrada en el periodo de selección (por ejemplo, el sujeto utiliza palabras aisladas, palabras asociadas como oraciones por combinación de dos palabras, lenguaje reducido o escaso o dificultad lingüística para entender).
    4. El sujeto o su padre, madre o tutor (si corresponde) da su consentimiento para participar en el estudio y proporciona consentimiento informado por escrito antes de que se realice ninguno de los procedimientos previstos en el estudio. Si el sujeto es menor de edad, se muestra dispuesto a otorgar su asentimiento cuando lo exijan las normas locales y siempre que se le considere capaz de hacerlo.
    5. Las mujeres en edad fértil en el momento de obtención del consentimiento o que lleguen a la edad fértil durante su participación en el estudio (a) deberán presentar una prueba de embarazo en orina negativa en el momento de la selección, (b) no podrán estar amamantando y (c) deberán comprometerse a utilizar un método anticonceptivo muy fiable (tasa teórica de fracasos inferior al 5 % anual) mientras dure el estudio y durante 30 días después de la última dosis de SBC-103. Se puede considerar que una mujer no es potencialmente fértil si aún no ha comenzado a tener la menstruación o se ha sometido a esterilización quirúrgica (es decir, histerectomía total o salpingooforectomía bilateral).
    6. Los varones deben comprometerse a utilizar un método anticonceptivo muy fiable (tasa teórica de fracasos inferior al 5 % anual) durante cualquier contacto sexual con mujeres en edad fértil mientras participan en el estudio y durante 30 días después de finalizar el estudio, aunque se hayan sometido a vasectomía con éxito.
    7. Disposición y capacidad para cumplir los requisitos del protocolo hasta donde se pueda esperar de un sujeto con deterioro cognitivo.

    Parte B
    Requisitos para la Parte B (tratamiento con 1 y/o 3 mg/kg)
    Los sujetos serán aptos para continuar el tratamiento con 1 y/o 3 mg/kg de SBC-103 ASA en la Parte B si no cumplen ninguno de los criterios de exclusión enumerados anteriormente y si cumplen los siguientes criterios:
    1. Finalización de la Parte A sin toxicidad incontrolable del fármaco del estudio,
    2. Se siguen cumpliendo los criterios de inclusión 4-7 anteriores y
    3. El CRS y el promotor han revisado los datos de seguridad del sujeto correspondientes a la Parte A y han determinado que es aceptable que el sujeto reinicie el tratamiento en la Parte B.

    Parte C
    Requisitos para la Parte C (tratamiento con 5 y/o 10 mg/kg)
    Los sujetos serán aptos para continuar el tratamiento con SBC-103 con una dosis más alta (5 o 10 mg/kg ASA) en la Parte C si no cumplen ninguno de los criterios de exclusión enumerados anteriormente y si cumplen los siguientes criterios:
    1. Finalización de al menos 4 dosis de 3 mg/kg en la Parte A o en la Parte B sin toxicidad incontrolable del fármaco del estudio; y
    2. Se siguen cumpliendo los criterios de inclusión 4-7 anteriores.
    E.4Principal exclusion criteria
    A subject who meets any of the following exclusion criteria will be ineligible to participate in this study:
    1. Received treatment with gene therapy at any time, or any investigational drug (including high dose genistein > 150 mg/kg/day), or device intended as a treatment for MPS IIIB within 30 days prior to Screening, or is currently being treated in another study that involves an investigational drug or device.
    2. Has any internal or non-removable external metal items that may present a safety risk for study assessments that utilize magnetic fields, or any other medical condition or circumstance in which an MRI is contraindicated according to local institutional policy.
    3. Previous hematopoietic stem cell or bone marrow transplant.
    4. Known or suspected hypersensitivity to anesthesia or the use of a sedative is contraindicated for any other reason.
    5. History of poorly controlled seizure disorder.
    6. A 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.
    7. Known hypersensitivity to eggs. Subjects at high risk for food allergy that may include eggs should be tested according to local guidelines.
    8. Other medical conditions or co-morbidities (eg, ALT or AST > 3x ULN, confirmed by repeat testing, analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual), or other markers of clinically significant liver dysfunction (eg. elevated bilirubin, [with the exception of patients with confirmed Gilberts Disease] confirmed by repeat testing, or elevated prothrombin time [PT]P/ International normalized ratio [INR] confirmed by repeat testing analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual) which in the opinion of the Investigator, in consultation with the Sponsor, would interfere with study compliance, or confound data interpretation.
    No se considerarán aptos para participar en el estudio los pacientes que cumplan alguno de los criterios siguientes:
    1. Tratamiento genético recibido en cualquier momento, o cualquier fármaco en investigación (incluidas dosis altas de genisteína > 150 mg/kg/día) o dispositivo diseñado como tratamiento para la MPS IIIB en el plazo de 30 días anteriores al periodo de selección, o en ese momento recibe tratamiento de otro estudio que implica fármacos o dispositivos en investigación.
    2. Tiene implantados elementos metálicos internos o externos fijos que pueden suponer un riesgo para la seguridad en el caso de evaluaciones del estudio que utilicen campos magnéticos, o cualquier otra circunstancia o trastorno médico en el que esté contraindicada la resonancia magnética (RM) conforme a las normas locales del centro.
    3. Trasplante previo de médula ósea o de células madre hematopoyéticas.
    4. Hipersensibilidad presunta o conocida a la anestesia o si el uso de un sedante está contraindicado por algún motivo.
    5. Antecedentes de trastorno convulsivo mal controlado.
    6. Trastorno hemorrágico o cualquier otra circunstancia o trastorno médico en el que esté contraindicada la punción lumbar (para la obtención de LCR) conforme a las normas locales del centro.
    7. Hipersensibilidad conocida a los huevos. Los sujetos que presenten alto riesgo de sufrir alergias alimentarias que puedan incluir los huevos requerirán pruebas específicas conforme a las normas locales.
    8. Otros trastornos médicos o enfermedades concomitantes (por ejemplo, alanina aminotransferasa [ALT] o aspartato aminotransferasa [AST] > 3 veces el límite superior de la normalidad [LSN], confirmado mediante pruebas repetidas, analizado en un laboratorio central o local y conforme al intervalo de referencia convencional proporcionado en el manual del laboratorio central) u otros marcadores de disfunción hepática clínicamente significativa (por ejemplo, bilirrubina elevada, [con la excepción de pacientes con enfermedad de Gilbert confirmada] confirmados por pruebas repetidas o niveles elevados de tiempo de protrombina [TP]/cociente internacional normalizado [CIN] confirmados por pruebas repetidas y analizados en un laboratorio central o local y conforme al intervalo de referencia convencional proporcionado en el manual del laboratorio central) que según el criterio del investigador, tras consultar al promotor, afectarían al cumplimiento del estudio o generarían confusión en la interpretación de los datos.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is safety and tolerability of SBC-103 in
    subjects with MPS IIIB. The safety assessments will include the following:
    ? Incidence of AEs, serious adverse events (SAEs), and infusion-
    associated reactions (IAR)s;
    ? Changes from baseline in clinical laboratory tests (hematology, serum chemistry, and urinalysis) and CSF findings (cell counts, glucose, and protein);
    ? Changes from baseline in 12-lead electrocardiograms (ECGs) ;
    ? Changes in vital signs during and post-infusion, relative to pre-infusion values;
    ? Physical examination findings;
    ? Use of concomitant medications/therapies;
    ? Assessment of ADAs, including seroconversion rate, time to seroconversion, and ADA titer by time point, peak ADA titer, and ADA titer status (positive/negative), and the effect of ADAs on the safety of SBC-103, including the relationship between ADA-
    positive subjects and the incidence of IARs.
    El criterio de evaluación principal en este estudio es la seguridad y tolerabilidad de SBC-103 en sujetos con MPS IIIB. Las evaluaciones de seguridad incluirán lo siguiente:
    - Incidencia de AA, acontecimientos adversos graves (AAG) y las reacciones-asociadas a la infusión (RAI).
    - Variaciones con respecto al momento basal en los análisis clínicos (hematología, bioquímica sérica y análisis de orina) y datos del LCR (recuentos de células, glucosa y proteína).
    - Variaciones en el electrocardiograma (ECG) de 12 derivaciones respecto al momento basal.
    - Variaciones de las constantes vitales durante y después de la infusión, en comparación con los valores previos -a la infusión.
    - Hallazgos de la exploración física.
    - Uso de medicamentos y tratamientos concomitantes.
    - Evaluación de anticuerpos contra el fármaco (ACF), que incluirá tasa de seroconversión, tiempo hasta seroconversión y título de ACF según el momento, título máximo de ACF y estado de título de ACF (positivo/negativo) y el efecto de ACF en la seguridad de SBC-103, incluida la relación entre sujetos con ACF-positivos y la incidencia de RAI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every two weeks
    Cada dos semanas
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are baseline and post-treatment measures
    of the following assessments:
    ? PK profile of SBC-103 after single and multiple doses:
    - Maximum observed serum concentration (Cmax)
    - Time to reach Cmax (Tmax)
    - Area- under- the- concentration-time -curve from time 0 to the last measurable time
    point (AUClast)
    - Area-under-the-concentration-time curve extrapolated to infinity (AUC?)
    - Half-life (T1/2)
    - Clearance (CL)
    - Volume of distribution at terminal phase (Vz)
    - Accumulation ratio (Rac)
    ? Effects of SBC-103 treatment on the onset, magnitude, and reversibility of changes in levels of total HS in CSF, serum, and urine.
    ? Neurocognitive and developmental function as determined by the scores on Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) and, as appropriate to the subject?s age, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, Second Edition (KABC-II), Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form (BOT-2 Brief Form), and Children?s Communication Checklist, Second Edition (CCC-2).
    ? Brain structure as determined by the relative proportion of grey and white matter volume and indices of microstructural integrity as assessed by MRI of the brain.
    ? Effect of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability and select PD/efficacy markers

    Exploratory endpoints in this study include measures to examine the onset, magnitude, and reversibility of changes in exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB disease characteristics, symptoms, and QOL after IV administration of SBC-103:
    * Biomarkers:
    ? Change in non-reducing end (NRE) HS derivatives in CSF, serum, and urine
    ? Changes in serum ferritin and chitotriosidase
    ? Changes in CSF-disease related biomarkers including but not limited to, hepatocyte growth factor (HGF), calbindin D, Tau, pTau, amyloid ?, albumin, IgG, glutamic acid, and glycine
    ? Changes in glutamic acid and glycine in relation to plasma (carrier-mediated excitatory amino acids that are markers of transport function)
    ? Changes in CSF/serum albumin index (CSF-AI).
    ? Changes in IgG index ( [CSF/serum IgG ratio] / [ CSF-AI] )
    ? Changes in inflammatory markers in serum
    * Disease characteristics, symptoms, and QOL
    ? Assessment of sleep disorders or dysfunction as determined by the Children's Sleep Habits Questionnaire (CSHQ)
    ? Assessment of behavior as determined by the Sanfilippo Behavior Rating Scale (SBRS)
    ? Assessment of subjective QOL as determined by the Short Form Health Survey for Children (SF-10)
    ? Assessment of caregiver QOL as determined by the Zarit Burden Interview (ZBI) 12 item short form
    ? Coarsening of features by Facial Dysmorphology Novel Analysis (FDNA)
    ? Additional blood or urine biomarkers of interest that are identified during the course of this study based on emerging data from the scientific literature or the Sponsor?s MPS IIIB development program (if there is sufficient sample volume and if local regulations permit).
    ? Assessment of genes that may contribute to and/or modify the disease phenotype via a DNA sample (where local regulations permit and subject to discretionary approval from each center?s Institutional Review Board [IRB)]/Independent Ethics Committee [IEC] and the consent/assent of the subject [and/or consent of the subject?s parent or legal guardian]).
    Los criterios de valoración secundarios de este estudio son las mediciones en el momento basal y después del tratamiento de las siguientes evaluaciones:
    - Perfil FC de SBC-103 después de dosis únicas y repetidas:
    - Concentración sérica máxima observada (Cmáx).
    - Tiempo hasta la Cmáx (Tmáx).
    - Área bajo la curva de concentración-tiempo desde el tiempo cero hasta el último momento de evaluación (AUCúlt).
    - Área bajo la curva de concentración-tiempo extrapolada hasta el infinito (AUC?).
    - Semivida (T1/2).
    - Aclaramiento (Cl).
    - Volumen de distribución en la fase terminal (Vz).
    - Índice de acumulación (Iac)
    - Efectos del tratamiento con SBC-103 sobre la aparición, la magnitud y la reversibilidad de los cambios en la concentración de HS total en LCR, suero y orina.
    - Función neurocognitiva y del desarrollo determinadas por las puntuaciones en Vineland-II y, según corresponda a la edad del sujeto, BSID-III o KABC-II, el Test Bruininks-Oseretsky sobre habilidades motrices, segunda edición, versión abreviada (BOT-2 Brief Form) y Lista de comprobación de la comunicación de los niños, segunda edición (CCC-2).
    - Estructura cerebral determinada por la proporción relativa del volumen de sustancia gris y blanca, y los índices de integridad microestructural evaluados mediante RM del cerebro.
    - Efecto de la interrupción temporal del tratamiento con SBC-103 (entre las Partes A y B) sobre la seguridad, tolerabilidad y determinados marcadores de FD/eficacia.

    Los criterios de valoración exploratorios de este estudio son examinar la aparición, magnitud y reversibilidad de cambios en biomarcadores exploratorios, la concentración de SBC-103 en LCR, las características de la enfermedad MPS IIIB, sus síntomas y la calidad de vida (CdV) tras la administración intravenosa de SBC103:
    *Biomarcadores:
    - Variaciones en derivados de HS de extremo no reductor en LCR, suero y orina
    - Variaciones en la ferritina y quitotriosidasa séricas
    - Variaciones en los marcadores del LCR relacionadas con la enfermedad, como por ejemplo, el factor de crecimiento de los hepatocitos (HGF), calbindina D, Tau, pTau, ?-amiloide, albúmina, inmunoglobulina G (IgG), ácido glutámico y glicina
    - Variaciones en el ácido glutámico y la glicina en relación con el plasma (transportadores- de aminoácidos excitadores que son marcadores de la función de transporte)
    - Variaciones en el índice de albúmina en suero/LCR (IA-LCR)
    - Variaciones en el índice de IgG ([índice de IgG en LCR/suero]/[IA-LCR])
    - Variaciones en los marcadores inflamatorios en suero
    * Características de la enfermedad, síntomas y CdV
    - Evaluación de la disfunción o los trastornos del sueño determinados por el cuestionario de hábitos del sueño infantil (Children's Sleep Habits Questionnaire [CSHQ])
    - Evaluación del comportamiento determinado por las Escalas de puntuación de conductas de Sanfilippo (SBRS)
    - Evaluación de la CdV subjetiva determinada por el Cuestionario de salud abreviado para niños (SF-10)
    - Evaluación de la CdV del cuidador determinada por el cuestionario de salud abreviado de 12 apartados de Zarit (Zarit Burden Interview [ZBI])
    - Acentuación los rasgos según el Facial Dysmorphology Novel Analysis [FDNA]
    - Biomarcadores de interés adicionales en sangre u orina que se identifiquen durante el transcurso de este estudio en función de los datos que aparezcan en la bibliografía científica o el programa de desarrollo de la MPS IIIB del promotor (si existe suficiente volumen de muestra y lo permite la legislación local).
    - Evaluación de los genes que podrían contribuir al fenotipo de la enfermedad o modificarlo mediante una muestra de ADN (donde lo permita la legislación local y sujeta a la aprobación discrecional del Comité ético de investigación clínica [CEIC] de cada centro y del consentimiento o asentimiento del sujeto [o el de su progenitor o tutor legal]).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every two weeks
    Cada dos semanas
    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 No
    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) No
    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 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.8.3 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 EEA2
    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
    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
    LVLS
    La última visita del último sujeto
    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 months10
    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 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) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 9
    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 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 with MPS IIIB disease are unable to consent for themselves due to the level of cognitive impairment.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    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)
    None.
    Ninguno
    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 Decision2016-04-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-13
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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