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    Summary
    EudraCT Number:2018-000195-15
    Sponsor's Protocol Code Number:P4-SAF-302
    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:2018-09-04
    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 number2018-000195-15
    A.3Full title of the trial
    An Open-Label, Single-Arm, Multicenter Study of Intracerebral Administration of Adeno-Associated Viral Vectors Serotype rh10 Carrying the Human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA for the Treatment of Mucopolysaccharidosis Type IIIA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label study with only one arm of treatment that will be carried out in different international sites of Intracerebral Administration of study drug for the Treatment of Sanfilippo syndrome type A
    A.4.1Sponsor's protocol code numberP4-SAF-302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03612869
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/078/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLysogene SA
    B.1.3.4CountryFrance
    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 supportLysogene SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLysogene SA
    B.5.2Functional name of contact pointSophie Olivier
    B.5.3 Address:
    B.5.3.1Street Address18-20 rue Jacques Dulud - Neuilly-sur-Seine
    B.5.3.2Town/ cityNeuilly-sur-Seine
    B.5.3.3Post code92200
    B.5.3.4CountryFrance
    B.5.4Telephone number+3363868 2337
    B.5.6E-mailsophie.olivier@lysogene.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/3/14/1389
    D.3 Description of the IMP
    D.3.1Product nameLYS-SAF302
    D.3.2Product code LYS-SAF302
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracerebral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNolenasufligene relduparvovec
    D.3.9.2Current sponsor codeLYS-SAF302
    D.3.9.3Other descriptive nameLYS-SAF302
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.4E+12
    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) Yes
    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
    Mucopolysaccharidosis Type IIIA
    E.1.1.1Medical condition in easily understood language
    Sanfilippo syndrome type A
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10056890
    E.1.2Term Mucopolysaccharidosis III
    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 assess the efficacy of intracranial delivery of AAVrh.10SGSH gene therapy (LYS-SAF302) in improving or stabilizing the neurodevelopmental status of MPS IIIA patients after 24 months (main cohort), compared to the expected evolution based on natural history data.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of intracranial delivery of LYS-SAF302 and to assess the treatment efficacy on the behavioral, sleep disturbances of the patients and on quality of life for both patient and parents.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    11. Documented MPS IIIA diagnosis based on genotyping confirming the SGSH gene mutations
    2. Age ≥ 30 months at screening (main cohort) or ≥6 months and < 30 months (ancillary cohort)
    3. Cognitive DQ score on BSID-III ≥ 50%
    4. Signed written informed consent before any study related procedure is performed
    5. Medical status sufficiently stable, in the opinion of the investigator, to adhere to the study visit schedule and other protocol requirements
    6. Confirmation by the study neurosurgeon and anesthesiologist of the feasibility of the neurosurgical procedure.
    E.4Principal exclusion criteria
    1. Homozygous for the S298P mutation or non-severe form of MPS IIIA, based on investigator’s judgement
    2. Participation in another gene or cell therapy clinical trial
    3. Past use of SGSH enzyme replacement therapy for a period exceeding 3 months. A washout period of at least 2 months is required prior to screening
    4. Current participation in a clinical trial of another investigational medicinal product.
    NOTE: Nutritional supplements, including Genistein at low dose (<150mg/Kg/day) are permitted if they are taken outside the context of an investigational trial
    5. History of bleeding disorder or current use of medications that, in the opinion of the investigator, place them at risk of bleeding following surgery
    6. Any condition that would contraindicate treatment with immunosuppressants such as
    tacrolimus, mycophenolate mofetil or steroids
    7. Rare and unrelated serious comorbidities e.g. Down syndrome, intraventricular hemorrhage in the new-born period, or extreme low birth weight (<1500 grams)
    8. History of poorly controlled seizure disorder
    9. Any vaccination 1 month prior to the planned surgery
    10. Visual or hearing impairment sufficient, in the clinical judgment of the investigator, to preclude cooperation with neurodevelopmental testing. Use of hearing aids is permitted.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy measurement is the comparison between the observed (post-surgery) evolution of cognitive development quotient (DQ) expressed by the ratio (DQ24/DQ0) between baseline and 24 months and the expected ratio calculated by applying a regression coefficient based on data from natural history studies.
    Cognitive DQ will be assessed by neurocognitive testing using the Bayley Scale for Infant and Toddler Development, 3rd Edition (BSID-III) or the Kauffman Assessment Battery for Children , 2nd Edition (KABC-II), depending on child’s age and ability. Primary and secondary analyses will be performed separately on the main and the ancillary cohorts.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint between baseline and 24 months.
    E.5.2Secondary end point(s)
    - The change from baseline in the cognitive development age (DA) and cognitive
    development quotient (DQ) assessed by neurocognitive tests (BSID III or KABCII)
    at all timepoints
    - The change from baseline in other DA and DQ (language and motor) assessed byneurocognitive tests (BSID III or KABC-II) at all timepoints
    -The percentage of patients with stabilized development age (DA) at 12 months and 24 months
    - The change from baseline in the total adaptive behavior composite standard score as measured by the Vineland Adaptive Behavior Scales (VABS-II) at 12 months and 24 months and change from baseline in total behavior problem as measured
    by the Child Behavior Checklist (CBCL) at 12 and 24 months
    - The change in sleep pattern as measured by the Children Sleep Habits Questionnaire (CSHQ) at 12 months and 24 months
    - The change from baseline in the patient/parent quality of life
    - The change from baseline in total cortical grey matter volume and white matter volume on MRI at 12 months and 24 months
    - The change from baseline in relevant disease biomarkers in CSF and PBMC
    E.5.2.1Timepoint(s) of evaluation of this end point
    BSID III, KABC-II and biomarkers will be assessed at all timepoints

    DA, VABS-II, CBCL, CSHQ, ITQOL-SF47, GHQ, HUI-3, PSI-4-SFMRI at 12 and 24 months for the main cohort. Corresponding timepoint of primary interest for the young cohort will be when all patients from the young cohort have reached 4 years of age.

    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 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) 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
    France
    Germany
    Netherlands
    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
    Subjects will be followed for 5 years post treatment for safety.
    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 months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    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: 20
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 14
    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
    Parental consent will be obtained.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 20
    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 will be followed for 5 years for safety.
    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 Decision2018-12-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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