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    Summary
    EudraCT Number:2019-004949-32
    Sponsor's Protocol Code Number:P1-GM-101
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-03-09
    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 number2019-004949-32
    A.3Full title of the trial
    An open-label adaptive-design study of intracisternal administration of adeno-associated viral vector serotype rh.10 carrying the human β-galactosidase cDNA for the treatment of GM1 gangliosidosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    LYS-GM101 gene therapy trial in patients with GM1 gangliosidosis
    A.4.1Sponsor's protocol code numberP1-GM-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04273269
    A.5.4Other Identifiers
    Name:INDNumber:19440
    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 SponsorLysogene
    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
    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/3/17/1851
    D.3 Description of the IMP
    D.3.1Product nameLYS-GM101
    D.3.2Product code LYS-GM101
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracisternal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNadeno-associated virus (AAV) serotype rh.10 expressing human betagalactosidase (AAVrh.10-CAG-βgal)
    D.3.9.2Current sponsor codeLYS-GM101
    D.3.9.3Other descriptive nameAdeno-associated virus serotype rh.10 expressing beta-galactosidase
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.8E+13
    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) No
    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
    GM1 gangliosidosis
    E.1.1.1Medical condition in easily understood language
    GM1 gangliosidosis
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    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
    Stage 1 (safety phase): The primary objective is to assess the safety/tolerability of intracisternal administration of LYS-GM101 in early and late infantile GM1 gangliosidosis patients.
    Stage 2 (confirmatory phase): The primary objective is to demonstrate efficacy of intracisternal administration of LYS-GM101 in early and late infantile GM1 gangliosidosis patients.
    E.2.2Secondary objectives of the trial
    Stage 1:
    - To collect preliminary efficacy data in infantile GM1 gangliosidosis.
    - To rank the primary and secondary efficacy endpoints and confirm timepoints of primary interest for Stage 2, based on natural history data and preliminary efficacy and/or biomarker data collected in infantile GM1 gangliosidosis patients during Stage 1
    Stage 2: To assess the safety and tolerability of LYS-GM101 in infantile GM1 gangliosidosis patients
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Video sub-study to capture disease hallmarks in home environment. Enrollment in the sub-study requires sign-off of a specific ICF and the download of an app for smartphone to record and transmit videos.
    See CAS-GM-101 Interview and Video Project attached to the package.
    E.3Principal inclusion criteria
    Stage 1: Safety phase
    1. Confirmed GM1 gangliosidosis diagnosis based on genotyping confirming the β-gal gene mutations and/or deficiency of β-gal enzymatic activity
    2. Study population:
    a. Children with early infantile GM1 gangliosidosis less than 12 months of age at screening and with swallowing ability (presence of feeding tube is permitted)
    b. Children with late infantile GM1 gangliosidosis less than 3 years of age at screening and with ability to sit with hand support or props)
    3. Signed written informed consent before any study related procedure is performed
    4. Patient medical status sufficiently stable and ability of parents/legal guardian, in the opinion of the Investigator, to adhere to the study visit schedule and other protocol requirements.

    Stage 2: Confirmatory phase
    Following DSMB review of 3-month safety from patients enrolled during the safety phase, enrollment in Stage 2 will be initiated. After the interim analysis on 6-month data of patients enrolled in the safety cohort, the final eligibility criteria for patients with early and late infantile GM1 gangliosidosis will be confirmed or may be revised based on the results of the interim analysis.
    E.4Principal exclusion criteria
    1. Uncontrolled seizure disorder. Patients who are stable on anticonvulsive medications may be included
    2. More than 40% brain atrophy as measured by total brain volume on MRI
    3. Current participation in a clinical trial of another investigational medicinal product
    4. Past participation in gene therapy trials
    5. History of hematopoietic stem cell transplantation
    6. Any condition that would contraindicate treatment with immunosuppressants
    7. Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection
    8. Presence of any permanent item (e.g., metal braces) precluding undergoing MRI
    9. History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results
    10. Rare and unrelated serious comorbidities, e.g. Down syndrome, intraventricular hemorrhage in the new-born period, extreme low birth weight (<1500 grams), or known bleeding disorders
    11. Any vaccination 1 month prior to immunosuppressant treatment
    12. Serology consistent with HIV exposure or consistent with active hepatitis B or C infection
    13. Grade 2 or higher lab abnormalities for LFT, bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT, and a PTT, according to CTCAE latest version (v5.0, dated 27 Nov 2017).
    E.5 End points
    E.5.1Primary end point(s)
    - In stage 1, the primary endpoint is safety/tolerability of LYS-GM101 drug product.
    - In stage 2, the primary endpoint is efficacy. Safety and preliminary efficacy data of patients included in stage 1 will condition enrollment in stage 2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Stage 1 (safety cohort): 4 first patients will receive a single dose of product. Enrollment in the stage 2 (confirmatory cohort) will start after review of the 3 month safety data of the first cohort by the DSMB.
    Three-month post administration of the 4 patients of the safety cohort, data will be reviewed by the DSMB. In the absence of unexpected safety signal, all additional patients enrolled in the study will receive the same dose in the confirmatory phase.
    Based on the rapidity of decline described in natural history data, it is anticipated that timepoints of primary interest will be at one and two years for early infantile and late infantile, respectively.
    E.5.2Secondary end point(s)
    The primary and secondary efficacy endpoints for early and late infantile
    GM1 gangliosidosis patients will be confirmed when the first 4 patients have reached 6-month follow-up (interim analysis). They will be selected among the efficacy variables collected during the dose escalation phase based on the interim analysis at 6 months and supported by the natural
    history studies and registry data. It is expected that selected endpoints for the confirmatory phase will differ based on GM1 gangliosidosis clinical type.
    In Stage 1, efficacy data will be analyzed as secondary endpoints. The data collected during and analyzed after Stage 1, as well as natural history data, will allow for ranking of the Stage 2 endpoints and time points. The selection of the primary endpoint for each subtype of GM1 gangliosidosis patients, the definition of all secondary endpoints and timepoints will be confirmed in a protocol amendment that will be submitted to regulatory and ethical authorities before implementation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Considering the different patterns of progression between the early infantile and late infantile forms, different primary endpoints and timepoints for each group of patients are likely to be selected for Stage 2.
    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 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
    Adaptive design
    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 EEA2
    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
    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
    Patients will be followed-up for 2 years post treatment for safety in this study.
    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
    E.8.9.2In all countries concerned by the trial years5
    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: 18
    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: 9
    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
    Paediatric population. Parental consent will be obtained.
    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 12
    F.4.2.2In the whole clinical trial 18
    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)
    All patients will be followed-up for 2 years.
    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 Decision2021-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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