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    Summary
    EudraCT Number:2013-002885-38
    Sponsor's Protocol Code Number:HGT-HIT-094
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-08
    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 number2013-002885-38
    A.3Full title of the trial
    A Controlled,Randomized,Two-arm,Open-label,Assessor-blinded,Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction with Elaprase® in Pediatric Patients with Hunter Syndrome and early Cognitive Impairment.
    Estudio controlado, aleatorizado, multicéntrico, de dos grupos, abierto, con enmascaramiento de los evaluadores de idursulfasa intratecal (IT) administrada junto con Elaprase® en pacientes pediátricos con síndrome de Hunter y deterioro cognitivo precoz
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Peadiatric study of Idursulfase-IT with Elaprase® in patients with Hunter Syndrome and early cognitive impairment
    Estudio pediátrico de idursulfasa-IT con Elaprase® en pacientes con síndrome de Hunter y deterioro cognitivo precoz
    A.4.1Sponsor's protocol code numberHGT-HIT-094
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/194/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorShire HGT 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 supportShire HGT
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire HGT
    B.5.2Functional name of contact pointNicole Rupprecht
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number0017814829559
    B.5.5Fax number0017824822955
    B.5.6E-mailnrupprecht@shire.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/3/01/078
    D.3 Description of the IMP
    D.3.1Product nameIdursulfase-IT
    D.3.2Product code HGT-2310
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIDURSULFASA
    D.3.9.1CAS number 50936-59-9
    D.3.9.2Current sponsor codeHGT-2310
    D.3.9.3Other descriptive nameidursulfase-IT
    D.3.9.4EV Substance CodeSUB22927
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Yes
    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 No
    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 Yes
    D.3.11.13.1Other medicinal product typeIdursulfasa-IT, enzima humana producida mediante ingeniería genética a partir de líneas celulares humanas.
    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
    Treatment of Hunter syndrome and cognitive impairment
    Tratamiento del síndrome de Hunter y deterioro cognitivo
    E.1.1.1Medical condition in easily understood language
    Hunter syndrome-Iduronate-2-Sulfatase enzyme deficiency
    Síndrome de Hunter: deficiencia de la enzima iduronato 2-sulfatasa
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10056889
    E.1.2Term Mucopolysaccharidosis II
    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 determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment on the General Conceptual Ability (GCA) score as measured by the Differential Ability Scale, Second Edition (DAS-II), in conjunction with Elaprase therapy
    Determinar el efecto de la pauta de tratamiento, administrada junto con Elaprase a pacientes pediátricos con síndrome de Hunter y deterioro cognitivo precoz, sobre la capacidad conceptual general (CCG) evaluada mediante el Cuestionario para la evaluación de las discapacidades, segunda edición (DAS II).
    E.2.2Secondary objectives of the trial
    Key secondary
    To determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment on the Adaptive Behavior Composite (ABC) score as measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), in conjunction with Elaprase therapy

    Secondary
    To determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment, in conjunction with Elaprase therapy, on:
    - Cognitive function as measured by the cluster areas and subtests of the DAS-II
    - Adaptive behavior as measured by the domains of the VABS-II

    For safety, device, PK/PD and health status see protocol section 2.4 - 2.6
    Secundario fundamental:
    Determinar el efecto de la pauta de tratamiento, administrada junto con Elaprase a pacientes pediátricos con síndrome de Hunter y deterioro cognitivo precoz, sobre el combinado de conducta adaptativa (CCA) evaluada mediante las Escalas de conducta adaptativa de Vineland, segunda edición (VABS II).

    Secundarios:
    Determinar el efecto de la pauta de tratamiento, administrada junto con Elaprase a pacientes pediátricos con síndrome de Hunter y disfunción cognitiva precoz, sobre los siguientes parámetros:
    - Función cognitiva, evaluada por las áreas agrupadas y las subpruebas del DAS II.
    - Conducta adaptativa, evaluada por los dominios de las VABS II.

    Para información sobre los objetivos de seguridad, del dispositivo, de la FC/FD y del estado de salud remítanse a la sección 2.4 - 2.6 del protocolo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction with Elaprase® in Pediatric Patients with Hunter Syndrome and Early Cognitive Impairment.
    Protocol Amendment 1 of 14 August 2013.

    The objective of the sub-study is:
    To examine the effect of the treatment regimen on safety and efficacy measures in pediatric patients with Hunter syndrome and early cognitive impairment who are below 3 years of age
    Estudio controlado, aleatorizado, multicéntrico, de dos grupos, abierto, con enmascaramiento de los evaluadores de idursulfasa intratecal (IT) administrada junto con Elaprase® en pacientes pediátricos con síndrome de Hunter y deterioro cognitivo precoz.
    Protocolo Enmienda 1 del 14 de agosto de 2013.

    El objeto del subestudio es:
    Investigar el efecto de la pauta de tratamiento sobre los parámetros de seguridad y eficacia en pacientes pediátricos con síndrome de Hunter y deterioro cognitivo precoz que sean menores de 3 años.
    E.3Principal inclusion criteria
    Inclusion Criteria for the Pivotal Study:
    - The patient is male and is >=3 and <18 years of age at the time of informed consent.
    Spanish-speaking patients who are to be assessed using the Spanish version of the DAS-II Early Years must be <7 years 8 months of age at the time of informed consent.
    - The patient must have a documented diagnosis of MPS II. Of the three criteria below, the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
    a. The patient has a deficiency in iduronate-2-sulfatase enzyme activity of <=10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on the reference laboratory's normal range).
    AND
    b.The patient has a documented mutation in the iduronate-2-sulfatase gene that leaves the FMR1 and FMR2 genes intact.
    OR
    c.The patient has a normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
    - The patient has evidence at Screening of Hunter syndrome-related cognitive impairment, defined as follows:
    A patient who is >=3 and <13 years of age must have one of the following criteria (3a OR 3b):
    a. A GCA score >=55 and <=85
    OR
    b. If the patient has a GCA score at Screening >85, there must be evidence of a decrease in GCA score of >=10 points over 12 months from a previously documented test result in observational study HGT-HIT-090.
    A patient who is >=13 and <18 years of age must have both of the following criteria (3c AND 3d):
    a. A GCA score of >=55 and <= 85.
    AND
    b. There must be evidence of a decrease in GCA score of >=10 points over 12 months from a previously documented test result in observational study HGT-HIT-090.
    - The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
    - The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the Investigator's judgment to complete the required protocol testing and must be compliant with wearing the hearing aid(s), if needed, on scheduled testing days.

    Inclusion criteria for the sub-study:
    - The patient is male and is <3 years of age at the time of informed consent.
    - The patient must have a documented diagnosis of MPS II. Of the three criteria below, the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
    a. The patient has a deficiency in iduronate-2-sulfatase enzyme activity of <=10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on the reference laboratory's normal range).
    AND
    b. The patient has a documented mutation in the iduronate 2 sulfatase gene that leaves the FMR1 and FMR2 genes intact.
    OR
    c. The patient has a normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
    - The patient has evidence at Screening of Hunter syndrome-related cognitive impairment as assessed using the BSID-III and defined as a composite score on the cognitive scale >=55 and <= 85.
    - The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
    - The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the Investigator's judgment to complete the required protocol testing and must be compliant with wearing the hearing aid(s), if needed, on scheduled testing days.
    Criterios de inclusión del estudio principal:
    - Ser varón y >=3 y <18 años de edad en el momento del consentimiento informado.
    Los pacientes hispanohablantes que vayan a evaluarse mediante la versión en español del DAS II Primeros años deben ser menores de 7 años y 8 meses de edad en el momento del consentimiento informado.
    - Tener un diagnóstico confirmado de MPS II. De los tres criterios siguientes, se aceptarán como diagnósticas de MPS II las combinaciones (2a Y 2b) o (2a Y 2c):
    a. Presentar una deficiencia de la actividad de la enzima iduronato 2 sulfatasa, determinada en plasma, fibroblastos o leucocitos, <=10 % del límite inferior del intervalo de la normalidad (según el intervalo de normalidad del laboratorio de referencia).
    Y
    b. Presentar una mutación documentada en el gen de la iduronato 2 sulfatasa que respete a los genes FMR1 y FMR2, que están intactos.
    O
    c. Presentar un nivel normal de actividad de otras sulfatasas, medido en plasma, fibroblastos o leucocitos (según el intervalo de normalidad del laboratorio de medición).
    - Presentar, en el momento de la selección, signos de deterioro cognitivo relacionado con el síndrome de Hunter, definido por lo siguiente:
    Los pacientes >=3 y <13 años de edad deberán cumplir uno de los siguientes criterios (3a O 3b):
    a. Puntuación de la CCG >=55 y <=85.
    O
    b. Si la puntuación de la CCG en la selección es >85, deberá haber pruebas de una reducción de la CCG >=10 puntos a lo largo de 12 meses con respecto al resultado de la evaluación previamente documentado en el estudio de observación HGT HIT 090.

    Los pacientes >=13 y <18 años de edad deberán cumplir los dos criterios siguientes (3c Y 3d):
    a. Puntuación de la CCG >= 55 y <=85.
    Y
    b. Debe haber pruebas de una reducción de la CCG >= 10 puntos a lo largo de 12 meses con respecto al resultado de la evaluación previamente documentado en el estudio de observación HGT HIT 090.

    - Haber recibido y tolerado un tratamiento con Elaprase® durante un mínimo de 4 meses en el período inmediatamente anterior a la selección.
    - Tener, a criterio del investigador, una capacidad auditiva suficiente, con audífonos en caso necesario, para realizar las evaluaciones exigidas en el protocolo, y utilizar los audífonos si se necesitan en los días en que estén programadas las evaluaciones.

    Criterios de inclusión del subestudio:
    - Ser varón y <3 años de edad en el momento del consentimiento informado.
    - Tener un diagnóstico confirmado de MPS II. De los tres criterios siguientes, se aceptarán como diagnósticas de MPS II las combinaciones (2a Y 2b) o (2a Y 2c):
    a. Presentar una deficiencia de la actividad de la enzima iduronato 2 sulfatasa, determinada en plasma, fibroblastos o leucocitos, <=10 % del límite inferior del intervalo de la normalidad (según el intervalo de normalidad del laboratorio de referencia).
    Y
    b. Presentar una mutación documentada del gen de la iduronato 2 sulfatasa que respete a los genes FMR1 y FMR2, que están intactos.
    O
    c. Presentar un nivel normal de actividad de otras sulfatasas, medido en plasma, fibroblastos o leucocitos (según el intervalo de normalidad del laboratorio de medición).

    - Presentar, en el momento de la selección, signos de deterioro cognitivo relacionado con el síndrome de Hunter, evaluado mediante las BSID III y definido como una puntuación combinada >=55 y <=85 en la escala cognitiva.
    - Haber recibido y tolerado un tratamiento con Elaprase® durante un mínimo de 4 meses en el período inmediatamente anterior a la selección.
    - Tener, a criterio del investigador, una capacidad auditiva suficiente, con audífonos en caso necesario, para realizar las evaluaciones exigidas en el protocolo, y utilizar los audífonos si se necesitan en los días en que estén programadas las evaluaciones.
    E.4Principal exclusion criteria
    - The patient has clinically significant non-Hunter syndrome-related CNS involvement (such as Fragile-X syndrome) which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
    - The patient has a large chromosomal deletion or complex rearrangement that includes a deletion of the FMR1 and/or FMR2 genes.
    - The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
    - The patient has contra-indications for performance of lumbar puncture such as musculoskeletal/spinal abnormalities or risk of abnormal bleeding.
    - The patient has a history of complications from previous lumbar punctures or technical challenges in conducting lumbar punctures such that the potential risks would exceed possible benefits for the patient.
    - The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O.
    - The patient has experienced infusion-related anaphylactoid event(s) or has evidence of consistent severe adverse events related to treatment with Elaprase which, in the Investigator's opinion, may pose an unnecessary risk to the patient.
    - The patient has received a cord blood or bone marrow transplant at any time or has received blood product transfusions within 90 days prior to Screening.
    - The patient has a history of poorly controlled seizure disorder.
    - The patient is unable to comply with the protocol (eg, has significant hearing or vision impairment, a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioral instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator.
    - The patient is enrolled in another clinical study that involves clinical investigation or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study.
    - The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to compromised airways or other conditions.
    - The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU), including:
    a. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device
    b. The patient's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator
    c. The patient's drug therapy requires substances known to be incompatible with the materials of construction
    d. The patient has a known or suspected local or general infection
    e. The patient is at risk of abnormal bleeding due to a medical condition or therapy
    f. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation
    g. The patient has a functioning CSF shunt device
    h. The patient has shown an intolerance to an implanted device
    - Presentar una afectación clínicamente importante del SNC sin relación con el síndrome de Hunter (como el síndrome del cromosoma X frágil) que, en opinión del investigador, pueda interferir en la cumplimentación e interpretación exactas de las evaluaciones del protocolo.
    - Presentar una delección cromosómica grande o un reordenamiento complejo que conlleve una delección de los genes FMR1 o FMR2.
    - Presentar trastornos concomitantes importantes, médicos o psiquiátricos, que pudieran afectar a los datos del estudio o confundir la integridad de los resultados del estudio.
    - Tener contraindicaciones para la realización de una punción lumbar, como anomalías musculoesqueléticas o vertebrales o riesgo de sufrir hemorragias anormales.
    - Tener antecedentes de complicaciones secundarias a punciones lumbares o de problemas técnicos para llevar a cabo la punción lumbar que hagan que los riesgos superen a los posibles beneficios para el paciente.
    - Presentar una presión de apertura del LCR en la punción lumbar superior a 30,0 cmH2O.
    - Haber sufrido episodios anafilactoides relacionados con la infusión o acontecimientos adversos graves relacionados con el tratamiento con Elaprase® que, en opinión del investigador, supongan un riesgo innecesario para el paciente.
    - Haber recibido trasplante de sangre de cordón umbilical o trasplante de médula ósea en cualquier momento, o transfusiones de hemoderivados en los 90 días previos a la selección.
    - Tener antecedentes de trastorno convulsivo mal controlado.
    - Ser incapaz de cumplir el protocolo (por ejemplo, tener una deficiencia auditiva o visual importante, una enfermedad clínicamente importante que dificulta la ejecución del protocolo, una situación social inestable o una inestabilidad psiquiátrica o de la conducta clínicamente importante, o no puede volver para las evaluaciones de seguridad o es improbable que complete el estudio por otros motivos), en opinión del investigador.
    - Participar en otro ensayo clínico que implique la investigación o el uso clínico de cualquier producto en investigación (fármaco o dispositivo intratecal/vertebral) en los 30 días previos a la inclusión en el estudio o en algún momento durante el mismo.
    - Presentar hipersensibilidad confirmada o presunta a los anestésicos, o una afectación de las vías respiratorias u otras enfermedades que conlleven un riesgo inaceptablemente alto para la anestesia.
    - Presentar alguna de las contraindicaciones que se indican en el manual de instrucciones del DAIM SOPH A PORT® Mini S, como por ejemplo:
    a. Haber presentado o poder presentar una reacción alérgica a los materiales de construcción del dispositivo SOPH A PORT® Mini S.
    b. Tener un tamaño corporal demasiado pequeño para soportar el tamaño del puerto de acceso SOPH A PORT® Mini S, según el criterio del investigador.
    c. Necesitar tratamiento farmacológico con sustancias incompatibles con los materiales de construcción.
    d. Presentar una infección local o general confirmada o presunta.
    e. Presentar riesgo de hemorragia anormal debida a una enfermedad o tratamiento.
    f. Tener una o más anomalías vertebrales que pudieran complicar la implantación o fijación segura.
    g. Tener un dispositivo de derivación del LCR en funcionamiento.
    h. Haber presentado intolerancia a un dispositivo implantado.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in the GCA score after 12 months of treatment, at Visit Week 52, as obtained by DAS-II testing
    Variación entre el momento basal y la semana 52, después de 12 meses de tratamiento, de la puntuación de la CCG obtenida mediante el DAS II.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, weeks 16, 28, 40 and 52
    Visita de selección, semanas 16, 28, 40 y 52
    E.5.2Secondary end point(s)
    - Change from baseline in the adaptive behavior composite (ABC) score after 12 months of treatment at Visit Week 52, as obtained by VABS-II testing
    - Change from baseline to Visit Weeks 16, 28, and 40 in the GCA score as obtained by DAS-II testing
    - Change from baseline to Visit Weeks 16, 28, and 40 in the ABC score as obtained by VABS-II testing
    - Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in cluster areas of the DAS-II: Verbal, Nonverbal, Spatial, and Special Nonverbal Composite (SNC)
    - Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores of the VABSII domains: Communication, Daily Living Skills, Socialization, and Motor Skills
    - Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, developmental quotients, and T-scores for the subtests of the DAS-II: Verbal Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, Matrices, and Copying for the DAS-II/Early Years and Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and Quantitative Reasoning for the DAS-II/School Years
    - Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, developmental quotients, and V-scale scores of the VABS-II subdomains: Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine)
    - Change from baseline to Visit Weeks 16, 28, 40, and 52 in the V-scale scores and observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its subscales (Internalizing, Externalizing)

    Pharmacokinetic and Pharmacodynamic Endpoints:
    - Serum concentration of idursulfase and serum PK parameters after IT administration
    - CSF concentration of idursulfase prior to each monthly IT administration
    - Change from baseline in the concentration of GAG in CSF

    Safety Assessments:
    Safety will be assessed during the study by collection of adverse events (by type, severity, and relationship to treatment [idursulfase-IT, the IDDD, device surgical procedure, or IT administration process] and IV Elaprase infusion), changes in clinical laboratory testing (serum chemistry, hematology, urinalysis), physical and neurological examination, vital signs, 12-lead ECG recordings, CSF laboratory parameters (chemistries, cell counts), anti-idursulfase antibodies in CSF and serum, and determination of antibodies having enzyme neutralizing activity.

    SOPH-A-PORT Mini S Device Assessments:
    SOPH-A-PORT Mini S assessments will include measures of device implantation, device function, device longevity, record of revisions, removals, and replacements of the implanted IDDD, and adverse events associated with the device. This data will be collected on the patient´s case report form (CRF) from the time of implantation and continue throughout the study as long as the SOPH-A-PORT Mini S remains implanted.

    - Health Status Assessment
    Health status dimensions as obtained by the EQ-5D questionnaire.
    - Variación entre el momento basal y la semana 52, después de 12 meses de tratamiento, de la puntuación del combinado de conducta adaptativa (CCA) obtenida mediante las VABS II.
    - Variación, entre el momento basal y las semanas 16, 28, y 40, de la puntuación de la CCG obtenida mediante el DAS II.
    - Variación, entre el momento basal y las semanas 16, 28, y 40, de la puntuación del CCA obtenida mediante el VABS-II.
    - Variación, entre el momento basal y las semanas 16, 28, 40 y 52, de las puntuaciones normalizadas de las áreas agrupadas del DAS II: verbal, no verbal, espacial y combinado no verbal especial (CNVE).
    - Variación, entre el momento basal y las semanas 16, 28, 40 y 52, de las puntuaciones normalizadas de los dominios de las VABS II: comunicación, destrezas para la vida cotidiana, socialización y habilidades motoras.
    - Variación, entre el momento basal y las semanas 16, 28, 40 y 52, de los equivalentes de edad, cocientes de desarrollo y puntuaciones T de las subcategorías del DAS II: comprensión verbal, semejanzas de imágenes, vocabulario denominativo, construcción del modelos, matrices y copia en el DAS II/Primeros años, y recuerdo de diseños, definición de palabras, construcción del modelos, matrices, semejanzas verbales y razonamiento secuencial y cuantitativo en el DAS II/Edad escolar.
    - Variación, entre el momento basal y las semanas 16, 28, 40 y 52, de los equivalentes de edad, cocientes de desarrollo y puntuaciones de la escala V de los subdominios de las VABS II: comunicación (receptiva, expresiva, por escrito), destrezas para la vida cotidiana (personal, doméstica, comunitaria), socialización (relaciones interpersonales, tiempo de juego y ocio, capacidad de adaptación) y habilidades motoras (gruesa y fina).
    - Variación, entre el momento basal y las semanas 16, 28, 40 y 52, de las puntuaciones de la escala V y los grados de inadaptación observados en el Índice de conducta inadaptada de las VABS II y sus subescalas (interiorización, exteriorización).

    Criterios de valoración farmacocinéticos y farmacodinámicos:
    - Concentración de idursulfasa en suero y parámetros farmacocinéticos séricos después de la administración IT.
    - Concentración de idursulfasa en el LCR antes de cada administración IT mensual
    - Variación de la concentración de GAG en el LCR con respecto al valor basal.

    Evaluaciones de la seguridad:
    La seguridad se evaluará durante el estudio mediante la recopilación de los acontecimientos adversos (por tipo, intensidad y relación con el tratamiento [idursulfasa IT, DAIM, intervención quirúrgica por el dispositivo, proceso de administración IT] y la infusión IV de Elaprase®), las anomalías analíticas (bioquímica sérica, hematología, análisis de orina), la exploración física y neurológica, las constantes vitales, el ECG de 12 derivaciones, los parámetros analíticos del LCR (bioquímica, número de células), los anticuerpos antiidursulfasa en LCR y suero y la determinación de anticuerpos neutralizantes de la actividad enzimática.

    Evaluaciones del dispositivo SOPH A PORT® Mini S:
    Las evaluaciones del SOPH A PORT® Mini S abarcarán parámetros de la implantación, el funcionamiento y la longevidad del dispositivo, el registro de las revisiones, retiradas y sustituciones del DAIM implantado y los acontecimientos adversos relacionados con el dispositivo. Estos datos se recogerán en el cuaderno de recogida de datos del paciente (CRD) desde el momento de la implantación y durante todo el tiempo del estudio que el SOPH A PORT® Mini S permanezca implantado.

    Evaluación del estado de salud
    Dimensiones del estado de salud obtenidas mediante el cuestionario EQ 5D.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Neurodevelopment assessments: screening, weeks 16, 28, 40 and 52

    For all other endpoints please refer to Appendix 1, 2 and 3 of the protocol.
    Valoraciones del neurodesarrollo: selección, semanas 16, 28, 40 y 52.

    Para todas las valoraciones remítanse a los Apéndices 1, 2 y 3 del protocolo.
    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 No
    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) 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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Los pacientes se asignan al azar para participar sin recibir tratamiento con IT
    Patients are assigned randomly to participate without receiving IT treatment
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States 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
    Argentina
    Mexico
    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
    The study will conclude after the last patient has completed his last visit.
    El estudio concluirá después de que el último paciente haya completado su última visita.
    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: 42
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 40
    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 No
    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
    minors
    menores
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 42
    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)
    An extension study is planned during which patients who complete HGT-HIT-094 and are eligible according to the inclusion/exclusion criteria for the extension study may continue, or begin, to receive IT treatment with idursulfase-IT via the SOPH-A-PORT Mini S device.
    Está planeado un estudio de extensión durante el que los pacientes que completen HGT-HIT-094 y sean elegibles según los criterios de inclusión/exclusión para el estudio de extensión pueden continuar, o empezar, recibiendo el tratamiento IT con idursulfasa-IT a través del producto sanitario SOPH-A-PORT Mini S.
    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 Decision2013-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-30
    P. End of Trial
    P.End of Trial StatusCompleted
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