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    Summary
    EudraCT Number:2014-004143-13
    Sponsor's Protocol Code Number:SHP-609-302
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2015-01-30
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-004143-13
    A.3Full title of the trial
    An Open Label Extension of Study HGT-HIT-094 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Idursulfase Administered in Conjunction with Elaprase® in Patients with Hunter Syndrome and Cognitive Impairment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An extension peadiatric study of Idursulfase-IT with Elaprase® in patients with Hunter Syndrome and early cognitive impairment
    A.4.1Sponsor's protocol code numberSHP-609-302
    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 SponsorShire Human Genetic Therapies, 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 pointSenior Clinical Project Manager
    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 number0017814820535
    B.5.6E-mailhfitch@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 INNIDURSULFASE
    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 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 Yes
    D.3.11.13.1Other medicinal product typeIdursulfase-IT, human enzyme produced from genetically engineered human cell line
    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
    Hunter syndrome and cognitive impairment
    E.1.1.1Medical condition in easily understood language
    Hunter syndrome-Iduronate-2-Sulfatase enzyme deficiency
    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 20.1
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10056917
    E.1.2Term Hunter'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
    The primary objective of this study is to evaluate long-term safety in subjects with Hunter syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT and intravenous (IV) Elaprase® enzyme replacement therapy (ERT)
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate long term clinical efficacy outcomes in subjects with Hunter syndrome and cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase therapy with respect to the following:
    • Cognitive function as measured by General Conceptual Ability (GCA), the cluster areas and subtests of the Differential Abilities Scale, 2nd edition (DAS-II) or the British Abilities Scales, Second Edition (BAS-II), or domains of the Bayley Scales of Infant Development, Third Edition (BSID-III)
    • Adaptive behavior as measured by the Adaptive Behavior Composite (ABC) score and standard domain scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
    • Brain structure volume as measured by magnetic resonance imaging (MRI)

    For PK/PD, health economics and outcome research and device objectives see protocol section 2.3 - 2.5.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects must have completed Visit Week 52 assessments in Study HGT-HIT-094
    2. The subject’s parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form after all relevant aspects of the study have been explained and discussed. Consent of the subject’s parent(s) or legally authorized guardian(s) and the subject’s consent/assent, as relevant, must be obtained
    3. The subject has continued to receive Elaprase on a regular basis in Study HGT-HIT-094
    E.4Principal exclusion criteria
    1. The subject has experienced, in the opinion of the Investigator, a safety or medical issue that contraindicates treatment with idursulfase-IT, including, but not limited to, uncontrolled seizure disorder, bleeding disorder, and clinically relevant hypertension
    2. The subject has a known hypersensitivity to any of the components of idursulfase-IT
    3. The subject has clinically relevant intracranial hypertension
    4. The subject is enrolled in another clinical study, other than HGT-HIT-094, that involves clinical investigations 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
    5. The subject 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.
    6. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use, including:
    a. The subject has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device
    b. The subject’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 subject’s drug therapy requires substances known to be incompatible with the materials of construction
    d. The subject has a known or suspected local or general infection
    e. The subject is at risk of abnormal bleeding due to a medical condition or therapy
    f. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation
    g. The subject has a functioning CSF shunt device
    h. The subject has shown an intolerance to an implanted device
    E.5 End points
    E.5.1Primary end point(s)
    Safety will be assessed during the study by the following:
    • adverse events (AEs) (by type, severity, and relationship to treatment [idursulfase-IT, the IDDD, device surgical procedure, or IT administration process], IV Elaprase infusion IV Elaprase and/or idursulfase-IT)
    • changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)
    • vital signs
    • 12-lead ECG recordings
    • CSF laboratory parameters (chemistries, cell counts)
    • anti-idursulfase antibodies in CSF and serum, including determination of anti-idursulfase antibodies having enzyme neutralizing activity
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse events (AEs) will be assessed during all the study. CSF assessments (other than standard chemistry) and clinical laboratory tests of blood and urine will be performed every 12 weeks. 12-lead ECG will be performed every 48 weeks.

    For all other endpoints please refer to Appendix 1 to 12 of the protocol.



    E.5.2Secondary end point(s)
    • Change from baseline in DAS-II standard scores: GCA, Special Nonverbal Composite (SNC); and standard cluster scores: Verbal, Nonverbal, Spatial; and/or the age equivalents and Development Quotient (DQ) from the BSID-III domains: Cognitive and Language
    • Change from baseline in standard composite scores of the VABS-II: ABC and domain standard scores: Communication, Daily Living Skills, Socialization, and Motor Skills
    • Change from baseline in age equivalents, developmental quotients, and T-scores for the core 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 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 in the v-Scale scores and observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its subscales (Internalizing, Externalizing)
    • Change from baseline in Brain Total Intracranial Volume, Brain Total Tissue Volume, Brain Total White Matter, Brain Total Gray Matter, and Total CSF Volume

    Health Economics and Outcomes Research Endpoints:
    • Health status dimensions as obtained by the EQ-5D-5L questionnaire
    • Health care resource utilization will be assessed using the HCUQ
    • Health-related quality of life for caregivers will be assessed using the CIQ
    • Functional status as obtained by the HS-FOCUS form

    Pharmacokinetic and Pharmacodynamic Endpoints:
    • Serum concentration of idursulfase and serum PK parameters after IT administration
    • CSF concentration of idursulfase
    • Change from baseline in the concentration of GAG in CSF
    • Change from baseline in the concentration of GAG in urine

    SOPH-A-PORT Mini S Assessments:
    The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, device function, device longevity, and AEs associated with the implant surgery or device. These data will be collected on the subject’s eCRF from the time of initial implantation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    *Initial Treatment Phase: Patients not treated in Study HGT-HIT-094 undergo neurodevelopmental assessment at week 16, 28, 40; EQ-5D-5L at week 4, 16, 28 and 40; Health Resource Utilization and Impact Questionnaire and HS-FOCUS at baseline, week 4, 16, 28 and 40.
    *Extended Treatment Phase:
    - Patients not treated in Study HGT-HIT-094 undergo all assessment above at week 52 and thereafter every 24 weeks.
    - Patients treated in Study HGT-HIT-094 do not undergo neurodevelopmental assessment and EQ-5D-5L at week 52 but thereafter every 24 weeks. Health Resource Utilization and Impact Questionnaire and HS-FOCUS will be performed at week 52 and thereafter every 24 weeks.

    For all other endpoints please refer to Appendix 1 to 12 of the protocol.
    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 Yes
    E.6.13.1Other scope of the trial description
    Quality of Life and Health Economics
    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 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.8.2.4Number 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 EEA4
    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
    Canada
    Colombia
    France
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    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: 56
    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: 55
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) 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
    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 18
    F.4.2.2In the whole clinical trial 54
    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
    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 Decision2015-03-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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