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    Summary
    EudraCT Number:2017-002187-40
    Sponsor's Protocol Code Number:GS-LHON-CLIN-05
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-02
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-002187-40
    A.3Full title of the trial
    A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected with G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year
    "Ensayo aleatorizado, con doble enmascaramiento y controlado con
    placebo en sujetos afectados con Neuropatía óptica hereditaria de Leber
    G11778A ND4 desde hace un año"
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of Bilateral Intravitreal Injection of GS010
    Eficacia y la seguridad de la inyección intravítrea bilateral de GS010
    A.3.2Name or abbreviated title of the trial where available
    REFLECT
    REFLECT
    A.4.1Sponsor's protocol code numberGS-LHON-CLIN-05
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03293524
    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 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.5.3.4CountryFrance
    B.5.4Telephone number34606214881
    B.5.5Fax number33149230116
    B.5.6E-mailipengue@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.3.8INN - Proposed INNlenadogene nolparvovec
    D.3.9.1CAS number 1640969-63-6
    D.3.9.2Current sponsor codeGS010
    D.3.9.3Other descriptive nameRecombinant Adeno-Associated Viral vector, serotype 2 (rAAV2/2) containing the human wild-type mitochondrial NADH Dehydrogenase 4 gene (ND4)
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1000000000000
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravitreal use
    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
    Neuropatía óptica hereditaria de Leber debido a mutaciones en el gen
    mitocondrial NADH deshidrogenasa 4
    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
    LHON: enfermedad genética del nervio óptico que conduce a pérdida
    visual y desarrollo de la ceguera
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    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
    To assess the efficacy of intravitreal GS010 compared to placebo
    intravitreal injection in second affected/not yet affected eyes, at 1-Year
    post-treatment, utilizing the change from baseline of the best-corrected
    visual acuity (BCVA) reported with the Log of the Minimal Angle of
    Resolution (LogMAR), in ND4 LHON subjects with vision loss up to one
    year.
    Evaluar la eficacia de la inyección de GS010 por vía intravítrea en
    comparación con la inyección de placebo por vía intravítrea en segundo
    ojo afectado/ojo aún no afectado, 1 año después del tratamiento,
    utilizando
    el cambio desde el inicio de la agudeza visual mejor corregida (AVMC)
    notificada con el logaritmo del mínimo ángulo de resolución (Log of the
    Minimal Angle of Resolution, LogMAR), en los sujetos con LHON en
    ND4 con pérdida de visión de hasta un año.
    E.2.2Secondary objectives of the trial
    Assess safety and tolerability of bilateral and unilateral intravitreal
    injection of GS010.
    Compare time course of the BCVA LogMAR response in second affected/not yet affected eyes treated with GS010 compared to placebo
    treatment.
    Assess the efficacy of intravitreal GS010 compared to placebo
    intravitreal injection in second affected/not yet affected eyes,
    compare the time course of the response in second affected/not yet
    affected eyes treated with GS010 compared to placebo treatment and to
    estimate the magnitude of the treatment effect at 1 and 2-years posttreatment
    Verify whether a difference exists at 1 and 2-years post-treatment,
    between first affected eyes and second affected/not yet affected eyes
    treated with GS010, utilizing both an intra-subject and inter-subject
    analysis.
    Assess rate of responders in first affected eyes treated with GS010
    Assess humoral and cellular immune responses
    Assess impact of bilateral intravitreal GS010 administration on Quality of
    Life
    Evaluar seguridad y tolerabilidad de la inyección bi y unilateral de GS010 intravítrea (IV)
    Comparar evolución temporal de respuesta del LogMAR AVMC en
    segundo ojo afectado/ aún no afectado tratado con GS010 en comparación con tto con placebo
    Evaluar eficacia de inyección IV de GS010 en comparación con
    inyección IV de placebo en segundos ojos afectados / no
    afectados,comparar tiempo de evolución de respuesta en segundos ojos
    afectados / no afectados tratados con GS010 en comparación con
    placebo y estimar magnitud del efecto del tto a 1 y 2 años después del
    tto
    Verificar si existe alguna diferencia 1 y 2 años después de tto entre
    primer ojo afectado y segundo ojo afectado/ojo aún no afectado tratado
    con GS010 utilizando análisis intrasujeto y entre sujetos
    Evaluar tasa de respondedores en los primeros ojos afectados tratados
    con GS010
    Evaluar respuestas inmunes humorales y celulares
    Evaluar impacto de administración bilateral IV de GS010 en calidad de
    Vida
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 15 years or older on the date of signed informed consent.
    2. Clinically manifested vision loss due to ND4 LHON, to any extent, in at
    least one eye.
    3. Vision loss duration of ≤ 365 days (i.e. ≤ 1 year) in each affected eye
    at Inclusion Visit
    (Visit 2).
    4. Female subjects (if of childbearing potential) must agree to use
    effective methods of birth control for up to 6 months after Treatment Visit(s) 3 and male subjects must agree to use condoms for up to 6 months after Treatment Visit(s) 3.
    5. Ability to obtain adequate pupillary dilation to permit thorough ocular
    examination and visual testing.
    6. Subject – and parent/legal guardian if the subject is under 18 years of
    age – has provided signed, written informed consent.
    1. Edad de 15 años o más en la fecha del consentimiento informado
    firmado.
    2. Pérdida de la visión clínicamente manifestada debido a ND4 LHON, en
    cualquier grado, en al menos un ojo
    3. Duración de pérdida de visión de ≤ 365 días (es decir, ≤ 1 año) en
    cada ojo afectado en la visita de inclusión (Visita 2).
    4. Las mujeres (en edad fértil) deben aceptar usar métodos efectivos de
    control de la natalidad hasta por 6 meses después de la visita de
    tratamiento 3 y los sujetos varones deben aceptar usar condones por hasta 6 meses después de la visita (s) de tratamiento 3.
    5. Capacidad de obtener una dilatación pupilar adecuada para permitir
    examen ocular completo y prueba visual.
    6. Sujeto - y padre / tutor legal si el sujeto tiene menos de 18 años de
    edad edad: ha proporcionado un consentimiento informado por escrito y
    firmado.
    E.4Principal exclusion criteria
    1. Any known allergy or hypersensitivity to GS010 or its constituents.
    2. Contraindication to intravitreal injection in any eye.
    3. Intravitreal drug delivery to any eye within 30 days prior to the
    Screening Visit (Visit 1).
    4. Previous vitrectomy in either eye.
    5. Narrow angle in any eye contra-indicating pupillary dilation.
    6. Presence of disorders or diseases of the eye or adnexa, excluding
    LHON, which may interfere with visual or ocular assessments, including SD-OCT, during the study period.
    7. Presence of known/documented mutations, other than the G11778A
    ND4 LHON-causing mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system.
    8. Presence of systemic or ocular/vision diseases, disorders or
    pathologies, other than LHON, known to cause or be associated with vision loss, or whose associated treatment(s) or
    therapy(ies) is/are known to cause or be associated with vision loss.
    9. Presence of optic neuropathy from any cause except LHON.
    10. 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 system, including Multiple Sclerosis (diagnosis of Multiple Sclerosis must be based on the 2010 Revisions to the McDonald Criteria [Polman 2011]).
    11. History of recurrent uveitis (idiopathic or immune-related) or active
    ocular inflammation.
    12. Participation in another clinical trial and receiving an IMP within 90
    days prior to the
    Screening Visit (Visit 1).
    13. Previous treatment with ocular gene therapy in either eye.
    14. Subjects refusing to discontinue idebenone.
    15. Subjects who have undergone ocular surgery of clinical relevance
    (per Investigator assessment) within 90 days preceding the Screening
    Visit (Visit 1).
    16. Female Subjects who are, or who intend to breast feed during the initial six months' postadministration of GS010.
    17. Subjects who unable to tolerate (e.g. the immune modulating
    regimen) or unable or unwilling to comply with all the protocol
    requirements.
    1. Cualquier alergia o hipersensibilidad conocida a GS010 o sus componentes. 2. Contraindicación a la inyección intravítrea en cualquier ojo. 3. Administración intravítrea de medicamentos a cualquier ojo dentro de los 30 días previos a la visita de detección (visita 1). 4. Vitrectomía previa en cualquier ojo. 5. Angulo estrecho en cualquier ojo que indique la dilatación pupilar. 6. Presencia de trastornos o enfermedades del ojo o anexos, excluyendo el LHON, que pueden interferir con las evaluaciones visuales u oculares, incluido SD-OCT, durante el período de estudio. 7. Presencia de mutaciones conocidas / documentadas, distintas de la mutación G11778A ND4 LHON-causante, que se sabe que causan patología del nervio óptico, la retina o el sistema visual aferente. 8. Presencia de enfermedades sistémicas u oculares / visuales, trastornos o patologías, distintas de LHON, que se sabe que causan o se
    asocian con la pérdida de la visión, o cuyos tratamientos asociados o la (s) terapia (es) causa (n) o se asocian con la pérdida de la visión. 9. Presencia de neuropatía óptica por cualquier causa excepto LHON.
    10. Presencia de enfermedad o enfermedad que, en opinión del
    Investigador, incluye síntomas y / o los tratamientos asociados pueden alterar la función visual, por ejemplo, cánceres o patologías del sistema nervioso central, incluida la esclerosis múltiple (el diagnóstico de esclerosis múltiple debe basarse en las revisiones de 2010 a los criterios de McDonald [Polman 2011]). 11. Antecedentes de uveítis recurrente (idiopática o relacionada con el sistema inmune) o activa inflamación ocular. 12. Participación en otro ensayo clínico y recibir un IMP dentro de los 90 días antes de la Visita de detección (visita 1). 13. Tratamiento previo con terapia génica ocular en cualquiera de los ojos. 14. Sujetos que se niegan a suspender la idebenona. 15. Sujetos que han sido sometidos a cirugía ocular de relevancia clínica (según la evaluación del investigador) dentro de los 90 días anteriores a la evaluación Visita (Visita 1). 16. Sujetos femeninos que están, o que tienen la intención de amamantar durante los primeros seis meses posteriores a la administración de GS010. 17. Sujetos que no pueden tolerar (por ejemplo, el régimen de inmunomodulación) o no puede o no quiere cumplir con todo el protocolo requisitos.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the BCVA reported with LogMAR at 1-Year
    post-treatment in second affected/not yet affected eyes of ND4 LHON
    subjects with vision loss up to one year. The change from baseline (Visit
    2) in second affected/not yet affected eyes receiving GS010 and placebo
    will be the primary response of interest. LogMAR BCVA will be used for
    statistical purposes
    El criterio de valoración principal será la AVMC comunicada con el
    LogMAR 1 año después del tratamiento en el segundo ojo afectado/ojo
    aún
    no afectado de los sujetos con LHON ND4 con pérdida de visión de hasta
    un año. El cambio desde el inicio (visita 2) en el segundo ojo
    afectado/ojo
    aún no afectado que recibe GS010 y placebo será la respuesta de interés
    principal. La AVMC del LogMAR se utilizará con propósitos estadísticos.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 1-Year post-treatment in second affected/not yet affected eyes of
    ND4 LHON subjects
    a 1 año después del tratamiento en el segundo ojo afectado / aún no
    afectado de Sujetos ND4 LHON
    E.5.2Secondary end point(s)
    LogMAR BCVA for second affected/not yet affected eyes receiving GS010
    versus placebo and also for first affected eyes receiving GS010. The
    change from baseline of the LogMAR BCVA will be used for statistical
    analyses.
    Response status over time for second affected/not yet affected eyes
    receiving GS010 versus placebo and also for first affected eyes receiving
    GS010.
    AVMC LogMAR para los segundos ojos afectados / aún no afectados que
    reciben GS010 versus placebo y también para los primeros ojos
    afectados que recibieron GS010. El cambio desde la línea de base de
    AVMC LogMAR se utilizará para análisis estadísticos
    Estado de respuesta en el tiempo para segundos ojos afectados / no
    afectados recibiendo GS010 versus placebo y también para los primeros
    ojos afectados que reciben GS010.
    E.5.2.1Timepoint(s) of evaluation of this end point
    BCVA : each timepoint of the follow-up period and at
    2-years post-treatment,
    Response status over time and at 1 and 2-years post-treatment.
    AVMC: cada punto de tiempo del período de seguimiento y en 2 años
    después del tratamiento,
    Estado de respuesta a lo largo del tiempo y a 1 y 2 años después del
    tratamiento.
    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 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) 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) 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 Yes
    E.8.2.3Other No
    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 EEA6
    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
    Belgium
    France
    Italy
    Netherlands
    Spain
    United Kingdom
    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
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 10
    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.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 90
    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
    SEGUIMIENTO ESTÁNDAR DE PACIENTES LHON
    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 Decision2018-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-16
    P. End of Trial
    P.End of Trial StatusOngoing
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