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    EudraCT Number:2015-001265-11
    Sponsor's Protocol Code Number:GS-LHON-CLIN-03A
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-11
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2015-001265-11
    A.3Full title of the trial
    A Randomized, Double-Masked, Sham-Controlled, Pivotal Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 (rAAV2/2-ND4) in Subjects Affected for 6 Months or Less by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation 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 III gene therapy clinical trial in LHON Subjects Affected for 6 Months or Less
    A.4.1Sponsor's protocol code numberGS-LHON-CLIN-03A
    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.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.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 pointRegulatory Affairs Director
    B.5.3 Address:
    B.5.3.1Street Address74 rue du Faubourg Saint-Antoine
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75012
    B.5.4Telephone number0033176217220
    B.5.5Fax number0033143142592
    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.3.8INN - Proposed INNpending
    D.3.9.1CAS number 1640969-63-6
    D.3.9.2Current sponsor coderAAV2/2-ND4
    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 typeequal
    D.3.10.3Concentration number1E12
    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. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of GS010 compared with sham at Week 48 in the change from baseline of the Log of the Minimal Angle of Resolution (LogMAR) in subjects affected for 6 months or less by LHON
    E.2.2Secondary objectives of the trial
    Evaluate the efficacy of GS010 compared with sham over the follow-up period and at Week 96 in the change from baseline of the LogMAR
    Verify whether the efficacy at Week 48 and at Week 96 of GS010
    compared with sham and measured by the change from baseline in the LogMAR is dependent upon the treatment of the better- or worse seeingeye Verify whether the rate of responders at Week 48 and 96 is dependent upon the treatment received and whether the magnitude of the treatment effect is dependent the treatment of the better- or worse seeing eye at entry
    Assess the effect of GS010 on parameters measured with high resolution spectral-domain optical coherence tomography (SD-OCT).
    Assess the effect of GS010 on standardized automated visual fields
    obtained with the Humphrey Visual Field (HVF) Analyzer II
    Assess the effect of GS010 on contrast sensitivity measured with the
    Pelli-Robson chart
    Assess the effect of GS010 on color vision measure with the Farnsworth- Munsell 100 Hue color test
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Selection criteria:
    1 Age 15 years or older
    2 Onset of vision loss based on medically documented history or
    subject testimony, in at least one eye for ≤180 days in duration and ifboth eyes are affected the duration of vision loss in both eyes must be ≤ 180 days in duration
    3 Each eye of the subject maintaining visual ability to allow at least for
    counting of the examiner's fingers at any distance
    4 Female subjects (if of childbearing potential) must agree to use
    effective methods of birth control up to 6 months after IVT injection and male subjects must agree to use condoms for up to 6 months after IVT injection
    5 Ability to obtain adequate pupillary dilation to permit thorough
    ocular examination and testing
    6 Signed written informed consent

    Inclusion Criteria:
    Subjects included in the study must satisfy all the following criteria at
    the Inclusion Visit (Visit 2).
    1 Documented results of genotyping showing the presence of the
    G11778A mutation in the ND4 gene and the absence of the other primary LHON-associated mutations (ND1 or ND6) in the subject's mitochondrial DNA
    2 Review of all selection criteria to ensure continued compliance
    3 Have a negative test for infection with human immunodeficiency
    virus (HIV)
    4 Have a negative pregnancy test for women of childbearing potential
    (a woman who is two years post-menopausal or surgically sterile is not
    considered to be of childbearing potential)
    E.4Principal exclusion criteria
    Non selection criteria:
    Subjects who meet at least one of the following criteria at the Screening Visit (Visit 1) will not be included into the study
    1 Any known allergy or hypersensitivity to GS010 or its constituents
    2 Contraindication to IVT injection
    3 IVT drug delivery to either eye within 30 days prior to the Screening
    Visit (Visit 1)
    4 Previous vitrectomy in either eye
    5 Narrow angle in either eye contra-indicating pupillary dilation
    6 Presence of disorders of the ocular media, such as the cornea and
    lens, which may interfere with visual acuity and other ocular
    assessments during the study period
    7 Vision disorders, other than LHON, involving visual disability or with
    the potential to cause further vision loss during the trial period.
    8 Causes of optic neuropathy other than LHON and glaucoma.
    9 Subjects with known mutations of other genes involved in
    pathological retinal or optic nerve conditions
    10 Presence of ocular or systemic disease, other than LHON and well-controlled glaucoma, whose pathology or associated treatments might affect the retina or the optic nerve
    11 History of amblyopia associated with a Snellen visual acuity
    equivalent of worse than 20/80 (equivalent to 6/24 at 6 meters, decimal acuity 0.25, LogMAR +0.6) in the affected eye
    12 Presence of ocular conditions, which in the opinion of the
    Investigator will prevent good quality SD-OCT imaging from being
    13. Presence, in either eye, of uncontrolled glaucoma, defined as an
    IOP greater than 25 mmHg, despite maximal medical therapy with IOP lowering agents
    14 Active ocular inflammation or history of idiopathic or autoimmune associated uveitis
    15 Subjects participating in another clinical trial and receiving an IMP
    within 90 days prior to the Screening Visit (Visit 1)
    16 Previous treatment with an ocular gene therapy product
    17 Subjects who have undergone ocular surgery of clinical relevance
    (per Investigator opinion) within 90 days preceding the Screening Visit
    (Visit 1)
    18 Female Subjects who are or who intend to breast feed during the
    trial period

    Exclusion criteria:
    Subjects who meet at least one of the following criteria at the Inclusion Visit (Visit 2) will not be included in the study
    1 Any non-selection criteria which may have appeared after the
    screening visit
    2 Subjects taking idebenone who have not completely discontinued the idebenone at least 7 days prior to Visit 2. If the subject has not
    discontinued idebenone at least 7 days prior to Visit 2, the visit may be delayed until the 7-day period is complete
    3 Presence, at the time of study inclusion, of infectious conjunctivitis,
    keratitis, scleritis or endophthalmitis in either eye
    4 Presence of systemic illness, including alcohol and drug abuse
    (except nicotine), or medically significant abnormal laboratory values
    that are deemed by the Investigator to preclude the subject's safe
    participation in the study
    5 Presence of illness or disease that, in the opinion of the Investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the central nervous
    6 Any medical or psychological condition that, in the opinion of the
    Investigator, may compromise the safe participation of the subject in the study or would preclude compliance with the study protocol or ability of the subject to successfully complete the study
    7 Subjects unable or unwilling to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the ETDRS visual acuity (quantitative
    score) at Week 48 after IVT injection. The subjects' LogMAR scores,
    which are derived from the number of letters they read on the ETDRS
    chart, will be used for statistical analysis purposes. The change from
    baseline in each eye will be the primary response of interest
    E.5.1.1Timepoint(s) of evaluation of this end point
    Full analysis = 48 weeks
    E.5.2Secondary end point(s)
    ETDRS visual acuity (quantitative score) over the follow-up period
    and at Week 96 after IVT injection. Change from baseline of the LogMAR
    scores will be used for statistical analysis purposes.
    Response status to treatment at Week 48 and 96 after IVT injection.
    Responder will be defined by an improvement of at least 15 letters in the visual acuity score obtained with ETDRS or being greater than a Snellen acuity equivalent of 20/200.
    Measure of parameters of high resolution SD-OCT of the posterior
    pole and optic nerve at Week 48 and Week 96 .
    Measure of the standardized automated visual fields obtained with
    HVF Analyzer II. Mean Deviation (MD) in decibels of sensitivity will be used at Week 48 and Week 96.
    Measure of contrast sensitivity with the Pelli-Robson chart at Week
    48 and Week 96.
    Measure of color vision with the Farnsworth-Munsell 100 Hue color
    vision test at Week 48 and Week 96
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be assessed 48 and 96 weeksafter 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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E. description
    E.8.2.4Number of treatment arms in the trial2
    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
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 7
    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) Yes
    F. of subjects for this age range: 7
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 40
    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 Decision2016-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-04
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