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    Summary
    EudraCT Number:2018-003291-12
    Sponsor's Protocol Code Number:SHP611-201
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-18
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-003291-12
    A.3Full title of the trial
    A Global, Multicenter, Open-label, Matched Historical Control Study of Intrathecal SHP611 in Subjects with Late Infantile Metachromatic Leukodystrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research study to determine the effects of an investigational drug, SHP611 on patients with with Late Infantile Metachromatic Leukodystrophy (MLD) specially the gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with MLD.
    A.4.1Sponsor's protocol code numberSHP611-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03771898
    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 Human Genetic Therapies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire Human Genetic Therapies, Inc.
    B.5.2Functional name of contact pointDavid Whiteman
    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 number001781482 9369
    B.5.5Fax number001781266 1365
    B.5.6E-maildavid.whiteman@takeda.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/3/10/813
    D.3 Description of the IMP
    D.3.2Product code SHP611
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeSHP611
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN ARYLSULFATASE A
    D.3.9.4EV Substance CodeSUB189761
    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 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 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
    Late Metachromatic Leukodystrophy (MLD)
    E.1.1.1Medical condition in easily understood language
    Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy).
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10067609
    E.1.2Term Metachromatic leukodystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of SHP611 on gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with MLD.
    If suitable controls cannot be matched despite the sponsor's best efforts, change from baseline results of GMFC-MLD at Week 106 will be compared with a pre-specified objective threshold to evaluate primary efficacy for this study.
    E.2.2Secondary objectives of the trial
    - To evaluate the effects of IT administration of SHP611 on gross motor function, using the Gross Motor Function Measure 88 (GMFM-88) total score in children with MLD
    - To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor functionusing GMFC-MLD
    - To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFM-88
    - To evaluate the effects of IT administration of SHP611 on expressive language using the Expressive Language Function Classification (ELFC
    MLD)
    - To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) biomarker (ie, sulfatides)
    - To evaluate the effects of IT administration of SHP611 on proton magnetic resonance spectroscopy (MRS) of the brain, specifically N acetylaspartate/
    Creatine (NAA/Cr) in white matter
    - To evaluate the effects of IT administration of SHP611 on Eichler MLD MRI severity score
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following criteria to be considered eligible for
    inclusion as a subject in the study:

    1. The subject must have a documented diagnosis of MLD (Groups A-E)
    a. Low ASA activity in leukocytes (compared to laboratory normal range)
    AND
    b. Elevated sulfatides in urine

    2. The subject must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by a pediatric neurologist or medical geneticist by 30 months of age (Groups A-C, and F) or be minimally symptomatic and >= 6 to <18 months of age (Group D), or be early symptomatic and >=12 to <18 months of age (Group E). Subjects in Group E must have neurological symptoms documented by a pediatric neurologist or medical geneticist.

    3. The subject’s age at the time of informed consent, must be:
     Group A: 18 to 48 months of age
     Group B: 18 to 72 months of age
     Group C: 18 to 72 months of age
     Group D: <18 months of age
    Group E: >=12 to <18 months of age
    Group F: 18 to 72 months of age

    4. The subject’s GMFC-MLD level at screening must be:
     Group A: GMFC-MLD level of 1 or 2
     Group B: GMFC-MLD level of 3
     Group C: GMFC-MLD level of 4
     Group D: minimally symptomatic, >=6 to 18 months of age, younger siblings of enrolled subjects, and have the same ASA allelic constitution
    Group E: GMFC-MLD level of 1 or 2 with a history of achieving stable walking (defined as at least 1 month of independent walking)
    Group F: GMFC-MLD level of 5 or 6

    5. The subject and his/her parent/representative(s) must have the ability to comply with the clinical protocol

    6. Subject's parent or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the subject

    Inclusion criteria for matched historical controls
    Subjects must meet all of the following criteria to be considered eligible for inclusion as a matched historical control:

    1. The subject must have a documented diagnosis of MLD
    a. Low ASA activity in leukocytes (compared to laboratory normal range)
    AND
    b. Elevated sulfatides in urine

    2. Subjects must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by 30 months of
    age

    3. Subjects must have at least 2 motor assessments by GMFC-MLD with the second assessment occurring at approximately 106 (±2) weeks after the first assessment or else a second assessment measured before Week 100 with a GMFC-MLD level 5 or 6. Subjects with GMFC-MLD data (pro or retrospectively determined) must have the earliest observation of level 1 or 2 (walking with support) in the data source-verified medical record

    4. Subjects must be 18 to 48 months of age at the earliest assessment
    E.4Principal exclusion criteria
    1. Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory’s normal range) or a known genetic disorder other than MLD

    2. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study

    3. Primary presentation of MLD was behavorial or cognitive symptoms of MLD (per investigator’s clinical judgment); behavioral symptoms that are
    secondary to motor deficits (eg: tantrums in response to loss of motor skills) are not exclusionary.

    4. The subject has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise

    5. Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study.

    6. Subjects with laboratory, ECG, or vital sign abnormalities reflecting intercurrent illness that may compromise their safety during the trial should not be enrolled. Abnormal laboratory, vital sign and ECG results at screening should be reviewed with the Shire medical monitor.

    7. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days or 5 half-lives (whichever is longer) prior to study enrollment or at any time during the study

    8. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU)
    a. The subject has had, or may have, an allergic reaction to the materials of construction
    b. The subject has shown an intolerance to an implanted device
    c. The subject's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port
    d. The subject's drug therapy requires substances known to be incompatible with the materials of construction
    e. The subject has a known or suspected local or general infection
    f. The subject is at risk of abnormal bleeding due to a medical condition or therapy
    g. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation
    h. The subject has a functioning CSF shunt device

    Exclusion criteria for matched historical controls:
    1. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes BMT, HSCT, or gene therapy at any point during the study

    2. Primary presentation of MLD was behavioral or cognitive symptoms of MLD (per investigator’s clinical judgment); behavioral symptoms that are
    secondary to motor deficits (eg; tantrums in response to loss of motor skills) are not exclusionary.
    3. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device)
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), evaluated as no greater than 2 levels decline from baseline in GMFC-MLD.
    If suitable controls cannot be matched despite the sponsor's best efforts, change from baseline results of GMFC-MLD at Week 106 will be compared with a pre-specified objective threshold to evaluate primary efficacy for this study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 years (week 106)
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints of this study are:
    - Response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), defined as a GMFM-88 total score >40.
    - Change from baseline at Week 106 of gross motor function, using the GMFC-MLD
    - Change from baseline at Week 106 of gross motor function, using the GMFM-88 total score GMFM-88 total score decline of no more than 20
    points from baseline and a total score that is ≥40 at Week 106
    - Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories, defined as any decline of more than 2-categories that has not
    reverted to a 2-category decline (or better) as of the last recorded observation
    - Time to unreversed decline from baseline in GMFM-88 total score of >20 points or unreversed decline to <40 points, whichever occurs first
    - Change from baseline at Week 106 in expressive language using the ELFC-MLD
    - Change from baseline at Week 106 in CSF sulfatides levels
    - Change from baseline at Week 106 in MRS metabolite levels, specifically: N-acetylaspartate/Creatine
    - Change from baseline at Week 106 in Eichler MLD MRI severity score
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 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 EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Brazil
    Canada
    France
    Germany
    Israel
    Japan
    Mexico
    Netherlands
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later.
    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 months7
    E.8.9.1In the Member State concerned days27
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days15
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 12
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    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 No
    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 No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children up to 72 months
    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 11
    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)
    Subjects who complete the study will be offered the opportunity to continue in a separate extension study (SHP611-202), provided that they meet the study eligibility criteria, where they may continue to receive treatment with SHP611 for an extended duration of time.

    For subjects who elect to discontinue the study, a safety follow-up visit will be conducted at Week 108 and the IDDD will be removed upon discontinuation from the study.
    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 Decision2019-04-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-20
    P. End of Trial
    P.End of Trial StatusOngoing
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