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    Summary
    EudraCT Number:2011-002044-28
    Sponsor's Protocol Code Number:HGT-MLD-070
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-06-28
    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 ConcernedGermany - BfArM
    A.2EudraCT number2011-002044-28
    A.3Full title of the trial
    A Phase I/II, Multicenter, Open-label, Dose Escalation Study of HGT-1110 Administered Intrathecally in Children with Metachromatic Leukodystrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A safety and efficacy study in Children with Metachromatic Leukodystrophy recieving enzyme (HGT-1110) replacement by intrathecal injection
    A.4.1Sponsor's protocol code numberHGT-MLD-070
    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 Genetics 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, 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 pointMelanie Ivarsson
    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 number0017814829101
    B.5.6E-mailmivarsson0@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/3/10/813
    D.3 Description of the IMP
    D.3.2Product code HGT-1110
    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.3.8INN - Proposed INNN/A
    D.3.9.2Current sponsor codeHGT-1110
    D.3.9.3Other descriptive nameRecombinant Human Arylsulfatase A (rhASA,
    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
    Treatment of Metachromatic Leukodystrophy
    E.1.1.1Medical condition in easily understood language
    Treatment of inherited arylsulfatase A 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 19.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Cohorts 1-3: to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks in children with metachromatic leukodystrophy

    Cohort 4: to determine the safety of HGT-1110 produced with a revised drug substance manufacturing process administered by IT injection for 38 weeks in children with MLD.
    E.2.2Secondary objectives of the trial
    • To evaluate the effects of IT administration of HGT-1110 on gross motor function
    • To evaluate the effects of IT administration of HGT-1110 on the ability to swallow
    • To evaluate the effects of IT administration of HGT-1110 on nerve conduction capabilities
    • To evaluate the effects of IT administration of HGT 1110 on adaptive behavior
    • To evaluate the effects of IT administration of HGT 1110 on health status and the ability to carry out activities of daily life
    • To assess single and repeated-dose pharmacokinetics of HGT-1110 in serum
    • To assess concentrations of HGT-1110 in cerebrospinal fluid
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For Cohorts 1-4:
    1. Confirmed diagnosis of metachromatic leukodystrophy by both:
    • Arylsulfatase A deficiency by assay in leukocytes
    AND
    • Elevated sulfatide in urine
    2. Appearance of the first symptoms of disease at or before 30 months of age.

    For Cohorts 1-3 only:
    3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to walk forward 10 steps with one hand held.
    4. The patient is less than 12 years of age at the time of screening.

    For Cohorts 4 only:
    3.1 Minimum motor function requirements:
    a. A total GMFM-88 (percent) score >= 40 at the screening examination and a total GMFM-88 (percent) score >=35 at the baseline examination
    AND
    b. GMFM-88 Dimension E: Walking, Running & Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screeening and baseline examinations (if applicable).
    4.1 The patient is less than 8 years of age at the time of screening

    For Cohorts 1-4:
    5. Neurological signs of MLD must be present at the screening examination.
    6. The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
    7. Patient’s parent(s) 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 patient.
    E.4Principal exclusion criteria
    Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening:
    For Cohorts 1-4:
    1. History of hematopoietic stem cell transplantation.
    2. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
    3. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
    4. The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study.
    5. The patient is pregnant or breastfeeding.
    6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use, 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 has a known or suspected local or general infection.
    d The patient is at risk of abnormal bleeding due to a medical condition or therapy.
    e The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
    f The patient has a functioning CSF shunt device.
    g The patient has shown an intolerance to an implanted device.
    E.5 End points
    E.5.1Primary end point(s)
    Safety will be measured by the following endpoints:
    • Reporting of treatment emergent adverse events
    • Change from baseline in clinical laboratory testing (serum chemistry including liver function tests, hematology, and urinalysis)
    • Change from baseline in 12–lead electrocardiograms, vital signs, physical examinations, and CSF chemistry (including cell counts, glucose, and protein)
    • Determination of the presence of anti-HGT 1110 antibodies in CSF and/or serum
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every other week up to week 42 (AEs, vital signs, CSF analysis)
    Once a month (serum chemistry, anti-HGT-1110 Abs, hematology)
    Screening and Week 40 (12-lead ECG)
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are the following:
    • Change from baseline in motor function using the GMFM-88 total score (percent)
    • Change from baseline in the ability to swallow as measured by the Functional Endoscopic Evaluation of Swallowing (FEES)
    • Change from baseline in nerve conduction as measured by the electroneurography (ENG) assessments of NCV, compound motor action potential (CMAP), amplitude (AMP), and distal latency (DL)
    • Change from baseline in the adaptive behavior composite standard score as measured by the Vinelan Adaptive Behavior Scales, Second Edition (VABS II)
    • Change from baseline in the domain specific Caregiver Observed MLD Functioning and Outcomes Reporting Tool (COMFORT) scores
    • Single and repeated-dose pharmacokinetic (PK) parameter estimates for HGT 1110 in serum
    • Concentrations of HGT-1110 in CSF at selected time points after single and repeated investigational drug product administration
    E.5.2.1Timepoint(s) of evaluation of this end point
    GMFM: Assessed at 0, 16, 28 and 40 weeks ((For cohort 4: also assessed
    at screening. The week 0 [baseline] assessment must be performed to
    confirm eligibility before device implantation or first dose
    administration, whichever occurs first ). FEES: Assessed at 0, 16, 28 and 40 weeks
    ENG studies : Assessed at 0, 16, 28 and 40 weeks
    VABS-II: Assessed at 0, 16, 28 and 40 weeks
    COMFORT: Assessed at 0, 16, 28 and 40 weeks
    Serum PK: Assessed on Week 0 and Week 38. Blood will be drawn for pharmacokinetic assessments within 1 hour prior to IT injection and then at 0.5, 1, 2, 4, 8, 12, 24 and 48 hours following completion of IT injection.
    CSF analysis: Assessed every other week for 40 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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) 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 Yes
    E.8.1.7.1Other trial design description
    Dose-escalation
    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 trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Denmark
    France
    Germany
    Japan
    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
    Last patient visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 24
    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: 9
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects who are under age and may have mental disabilities
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 24
    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)
    Patients who complete all study requirements in Study HGT-MLD-070 may be eligible to participate in an extension study, if offered. However, patients are not obligated to participate in any additional studies, and the sponsor cannot guarantee that such studies will occur.
    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 Decision2011-10-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-01-20
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