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    Summary
    EudraCT Number:2013-001405-90
    Sponsor's Protocol Code Number:GS-LHON/CLIN/01
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-02-18
    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 ConcernedFrance - ANSM
    A.2EudraCT number2013-001405-90
    A.3Full title of the trial
    A phase I/IIa, non randomized, escalating dose, open-label study to evaluate safety and efficacy of GS010 (rAAV2/2-ND4) in patients suffering from Leber Hereditary Optic Neuropathy due to mutations in the mitochondrial NADH Dehydrogenase 4 gene
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/IIa gene therapy clinical trial in LHON patients
    A.4.1Sponsor's protocol code numberGS-LHON/CLIN/01
    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 SponsorGENSIGHT-BIOLOGICS
    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 supportGENSIGHT-BIOLOGICS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGENSIGHT-BIOLOGICS
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address89 rue du Faubourg Saint-Antoine
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75011
    B.5.3.4CountryFrance
    B.5.4Telephone number0033665038601
    B.5.6E-mailagaly@gensight-biologics.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/3/11/860
    D.3 Description of the IMP
    D.3.1Product nameRecombinant AAV vector serotype 2 containing the human wild type mitochondrial ND4 gene
    D.3.2Product code GS010
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravitreal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameRAAV2/2-ND4 VECTOR
    D.3.9.4EV Substance CodeSUB129740
    D.3.10 Strength
    D.3.10.1Concentration unit titre titre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number6.3E11 to 2.0E13
    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 Yes
    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
    Leber Hereditary Optic Neuropathy due to mutations in the mitochondrial NADH Dehydrogenase 4 gene
    E.1.1.1Medical condition in easily understood language
    LHON: Genetic disease of the optic nerve which leads to visual loss and development of blindness
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10062951
    E.1.2Term Leber's hereditary optic atrophy neuropathy
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of the safety and tolerability of a single intravitreal (IVT) injections of escalating doses of GS010 (9xE09 vg, 3xE10 vg and 9xE10 vg) in patients suffering from Leber Hereditary Optic Neuropathy (LHON) due to mutation G11778A in the mitochondrial NADH Dehydrogenase 4 (ND4) gene
    E.2.2Secondary objectives of the trial
    Evaluation of the efficacy on visual functional criteria
    Evaluation of the eye fundus
    Evaluation of the immunogenicity of GS010 in terms of humoral and cellular immune response
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4
    2. Age 18 years old or older at the time of study entry (informed consent signature)
    3. Visual acuity ≤ 1/10 of the less functional eye
    4. Visual acuity ≤ 3/10 of the less functional eye for the patients of cohort 4 only
    5. Sufficient viable retinal ganglion cells (RGC) as determined by optical coherence tomography (OCT): Retinal nerve fiber layer (RNFL) thickness estimation ≤ 80 μm
    6. No infection with Human Immunodeficiency Virus (HIV)
    7. Negative pregnancy test in women of childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential)
    8. Female patients (if childbearing potency) must agree to use an effective methods of birth control during 6 months after the end of treatment
    9. Affiliated to or a beneficiary of the French health care system
    10. Written informed consent
    E.4Principal exclusion criteria
    11. Any known allergy or hypersensibility to one of the product used during the trial
    12. Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…)
    13. Disorder of the ocular humors and of the internal retina involving visual disability
    14. Glaucoma
    15. Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve
    16. Vascular retinal occlusion
    17. Narrow angle contra-indicating pupillary dilation
    18. Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...)
    19. Patients presenting known mutation of other genes implicated in pathological retinal conditions
    20. Patients treated by oral corticoids within 14 days prior inclusion at study entry.
    21. Patients who had received Idebenone during the 2 months preceding the injection.
    22. Participation in any other clinical trial on the eye within 3 months preceding the injection and during the study period
    23. Patients who had eye surgery within the last 3 months preceding the inclusion
    24. Patients suffering from any systemic illness or showing medically significant abnormal laboratory values at screening
    25. Absence of vision on the other contralateral eye
    26. Patients affected by pathologies for which the symptoms and/or the associated treatments can alter the visual function, for instance cancers or any pathology of the central nervous system
    27. Diabetes patients with symptoms of retinopathy or macula oedema,
    28. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study
    29. Patient unable or unwilling to comply with the protocol requirements
    E.5 End points
    E.5.1Primary end point(s)
    Overall incidence of adverse events will be evaluated for each dose level (9xE09 vg, 3xE10 vg or 9xE10 vg), and for the study as a whole. Similarly, the incidence of serious adverse events will be monitored. An interim complete safety analysis will be performed at 24 weeks of follow-up after the injection of the last subject of the 4rd cohort. In addition, a full analysis will be done 48 weeks after the injection of the last included subject.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Interim analysis = 24 weeks
    Full analysis = 48 weeks
    E.5.2Secondary end point(s)
    Efficacy by measuring the central visual function as assessed by the visual acuity and visual field 48 weeks after the injection (ETDRS scale, vision test, Computerized visual field)
    Efficacy on visual criteria overtime, relative to baseline measured by:
    - Computerized visual field (Humphrey 24.2) to measure visual field (threshold and mean deviation)
    - Computerized visual field (Octopus) to measure central scotoma
    - Fundus perimetry measured with micro perimeter
    - Optical Coherence Tomography (OCT) to measure 360° and each quadrant thickness of peripapillary retinal nerve fiber layer (RNFL)
    - Visual evoked potential (VEP) to measure latency and amplitude
    - Pattern Electroretinogram (PERG) to measure peak time and amplitude
    - Color vision measured by Computer graphic method
    Evaluation of the eye fundus by OCT and fundus imaging overtime, relative to baseline
    Cellular and humoral (total and/or neutralizing antibodies) response to AAV2 will be measured
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be assessed 48 weeks after the injection of GS010.
    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 No
    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 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 years2
    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 years2
    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 No
    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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    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 Yes
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    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)
    Standard follow-up of LHON patients
    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 Decision2013-12-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-25
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