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    Summary
    EudraCT Number:2011-004410-42
    Sponsor's Protocol Code Number:C11-09
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-12-19
    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 ConcernedFrance - ANSM
    A.2EudraCT number2011-004410-42
    A.3Full title of the trial
    A phase I/II, open labeled, monocentric study of direct intracranial administration of a replication deficient adeno-associated virus gene transfer vector serotype rh.10 expressing the human ARSA cDNA to children with metachromatic leukodystrophy
    Etude de phase I/II, monocentrique, ouverte, de l’administration intracérébrale
    directe de vecteur viral associé à l’adénovirus de sérotype rh10
    (VAArh10) deficient pour la réplication, codant l’ADNc du gène ARSA
    humain chez des enfants atteints de leucodystrophie métachromatique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intracerebral Gene Therapy for MLD
    Thérapie génique intracérébrale pour la Leucodystrophie Métachromatique
    A.3.2Name or abbreviated title of the trial where available
    Intracerebral Gene Therapy for MLD
    A.4.1Sponsor's protocol code numberC11-09
    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 SponsorInserm
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFrench ministry of research: PHRC (hospital program for clinical research)
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInserm
    B.5.2Functional name of contact pointAnne PUECH
    B.5.3 Address:
    B.5.3.1Street AddressInstitut Santé Publique - 101 rue de Tolbiac
    B.5.3.2Town/ cityParis Cedex 13
    B.5.3.3Post code75654
    B.5.3.4CountryFrance
    B.5.4Telephone number00144236047
    B.5.5Fax number00144236710
    B.5.6E-mailrqrc.siege@inserm.fr
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAAVrh.10cuARSA
    D.3.2Product code Non applicable
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntracerebral use
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Early onset forms of MLD
    E.1.1.1Medical condition in easily understood language
    Early onset forms of Metachromatic Leucodystrophy.
    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 14.1
    E.1.2Level SOC
    E.1.2Classification code 10029205
    E.1.2Term Nervous system disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10027433
    E.1.2Term Metabolism and nutrition disorders
    E.1.2System Organ Class 10027433 - Metabolism and nutrition 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 goal of the trial is the assessment of tolerance (safety) of the intracerebral adminsitration of a single dose of AAVrh.10cuARSA
    E.2.2Secondary objectives of the trial
    Evaluate the efficacy of intracerebral administration of a single dose of a AAVrh.210cuARSA to stop the disease progression
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Boys or girls with an ealry onset form of MLD
    - Age between 6 months ans 4 years, inclusive
    - Interval between age of first symptoms and age of inclusion muyst be 12 or less months
    - Diagnostic of MLD based on the measurement of ARSA activity in leukocytes and the accumulation of sulfatides in urine, along with normal activity of at least one other sulfatase
    - Informed consent signed up and willingness for monitoring 2 years after treatment
    - Normal values for standard laboratory tests.
    E.4Principal exclusion criteria
    - Absence of ARSA protein by immunocytochemistry and/or ELISA
    - Gestational age < 32 weeks of amenorrhoea and age < 1 year
    - Brain atrophy with a subdural space > 10mm in the frontal region.
    -MLD MRI severity score >14
    - Performance IQ<70 at WPPSI-III or cognitive function < 3rd percentile at the Bayley's test of infant development
    - If age>16 months at inclusion, inability to walk few steps alone OR inability to walk few steps with support on one side along with inability to stand up alone
    - Impossibility for anesthesia
    - Malignancy cardiac malformation, liver dysfunction, or renal dysfuncion
    - Neurological disorder, except benign, not related to MLD
    - Any other clinically significant untreated co-morbid medical condition as determined by the clinical investigator, including cardiac, pulmonary or kidney disease.
    - MRI impossibilty
    - Evoked potential impossibility
    - Participation to another therapeutic clinical trial for MLD
    - Unaffiliated to any French health insurance or any other European National Health Insurance
    E.5 End points
    E.5.1Primary end point(s)
    A) SAFETY
    Early follow-up: safety or neurosurgical procedure (M0-M1)
    - Standard clinical and neurological exam and monitoring of adverse events associated to the procedure
    - Standard laboratory tests
    - CT scan
    - Brain MRI
    Follow-up after the neurosurgical procedure (M1-M24)
    - Standard clinical and laboratory tests and adverse event monitoring
    - Brain MRI

    B) Primary efficacy endpoint
    MLD neurological severity score
    E.5.1.1Timepoint(s) of evaluation of this end point
    A) SAFETY
    Early follow-up: safety or neurosurgical procedure (M0-M1)
    - Standard clinical and neurological exam and monitoring of adverse events associated to the procedure: day +1, +3, +7, +10 and months +1
    - Standard laboratory tests: day +3, +10, and months +1
    - CT scan: within 36 hours of the procedure
    - Brain MRI day +6 and month +1
    Follow-up after the neurosurgical procedure (M1-M24)
    - Standard clinical and laboratory tests and adverse event monitoring months 1,3,6,9,15 18 and 24
    - Brain MRI months +3, +9, +15 and +24

    B) Primary efficacy endpoint
    MLD neurological severity score at months +1, +3, +6, +12 +18 and +24
    E.5.2Secondary end point(s)
    Motor scores (GMFM, Ashworth and ICARS)
    Neurological evaluation
    Cognitive functions (Bayey Scales of Infant Development
    MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy
    Neuroelectrophysiological tests (peripheral nerve condution velocity, visual, auditory and somatosensory evoked potentials)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Motor scores (GMFM, Ashworth and ICARS): at months +1, +3 for GMFM ans Ahshworth tests only, and +6, +12, +18and +24 for all tests
    Neurological evaluation at each visit.
    Cognitive functions (Bayey Scales of Infant Development at months +3, +9, +15 and +24.
    MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy at months +1, +3, +6, +9, +15 and +24.
    Neuroelectrophysiological tests (peripheral nerve condution velocity, visual, auditory at months +3, 15 and +24 and somatosensory evoked potentials)
    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 No
    E.6.7Pharmacodynamic No
    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) 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 No
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 5
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    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
    children of age between 6 months ans 4 years inclusive.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    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)
    Clinical, neurological, neuroimaging and electrophysiological monitoring will be done every six months for three years and then annually for life.
    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 Decision2012-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-20
    P. End of Trial
    P.End of Trial StatusOngoing
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