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Efficacy and Safety Study of Bilateral Intravitreal Injection of GS010 for the Treatment of Vision Loss up to 1 Year From Onset in LHON Due to the ND4 Mutation (REFLECT)

This study is not yet open for participant recruitment.
Verified September 2017 by GenSight Biologics
Sponsor:
ClinicalTrials.gov Identifier:
NCT03293524
First Posted: September 26, 2017
Last Update Posted: September 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
GenSight Biologics
  Purpose
The goal of this clinical trial is to assess the safety and efficacy of GS010, a gene therapy, in improving the retina functional & structural outcomes in subjects with LHON due to the G11778A ND4 mitochondrial mutation when vision loss duration is present up to one year.

Condition Intervention Phase
Leber Hereditary Optic Neuropathy (Optic, Atrophy, Hereditary, Leber) Genetic: GS010 Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year

Resource links provided by NLM:


Further study details as provided by GenSight Biologics:

Primary Outcome Measures:
  • Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year [ Time Frame: at 1-Year post baseline treatment ]
    The primary endpoint will be the BCVA reported with LogMAR at 1-Year post-treatment in second affected/not yet affected eyes. The change from baseline 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.


Secondary Outcome Measures:
  • Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years [ Time Frame: at 2-Years post baseline treatment ]
    LogMAR BCVA at each timepoint of the follow-up period and at 2-years post-treatment, 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.

  • Responder Analysis [ Time Frame: at 1-Year and 2-Years post baseline treatment ]

    Response status over time and at 1 and 2-years post baseline treatment. Response status will be assessed for second affected/not yet affected eyes receiving GS010 versus placebo and also for first affected eyes receiving GS010. Definitions of responder eyes include:

    1. Eyes whose LogMAR BCVA improves (i.e. decreases) by ≥ 0.3 LogMAR (equivalent to a gain of ≥ 15 ETDRS letters) compared to baseline.
    2. Eyes whose LogMAR BCVA does not increase (i.e. worsen) by ≥ 0.3 LogMAR (equivalent to eye that lose ≤ 15 ETDRS letters) compared to baseline.
    3. Eyes whose LogMAR visual acuity is < 1.0 (i.e. better than LogMAR 1.0, equivalent to better than Snellen acuity of 20/200).

  • Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with SD-OCT over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

  • Humphrey Visual Field (HVF) parameter [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with HVF 30-2 over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

  • Pelli Robson Low Vision Contrast Sensitivity parameter [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with Pelli Robson Low Vision Contrast Sensitivity over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

  • Quality of Life: Visual Functioning Questionnaire-25 [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Visual Functioning Questionnaire-25 at 1 and 2-years post-treatment

  • Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment.


Other Outcome Measures:
  • Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: up to 2-Years post baseline treatment ]
    Adverse events (AEs) and serious adverse events (SAEs), including those that are treatment-emergent and non-treatment-emergent, throughout the study period and at each study visit. Incidence and severity of systemic and local (ocular) AEs and SAEs will be determined at each clinical site and for the entire study cohort.

  • Physical examinations [ Time Frame: At 2-Years post baseline treatment ]
    Results of physical examinations

  • Electrocardiograms [ Time Frame: At 2-Years post baseline treatment ]
    Results of Electrocardiograms (ECGs)

  • Laboratory results [ Time Frame: At 2-Years post baseline treatment ]
    Results of laboratory tests from blood collection

  • Immune response evaluations [ Time Frame: Up to 2-Years post baseline treatment ]

    Results of immune response evaluations

    1. Time course of the humoral immune response measured with Neutralizing Antibodies (Nab) against Adeno-associated virus vector 2 (AAV2)
    2. Time course of the cellular immune response against AAV2

  • Blood Bio-dissemination of AAV2 Vector DNA [ Time Frame: up to 4 weeks post-treatment ]
    Results of bio-dissemination testing up to 4-weeks post-treatment


Estimated Enrollment: 90
Anticipated Study Start Date: December 30, 2017
Estimated Study Completion Date: June 30, 2021
Estimated Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Arm 1
Subjects will be randomized to treatment arm 1 or treatment arm 2 in a 1:1 allocation. Subjects in treatment arm 1 will receive intravitreal GS010 in both eyes.
Genetic: GS010
GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 will be administrated via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) as a single baseline intravitreal injection.
Placebo Comparator: Treatment Arm 2
Subjects will be randomized to treatment arm 1 or treatment arm 2 in a 1:1 allocation. Subjects in treatment arm 2 will receive GS010 in one eye and placebo intravitreal injection in the other eye.
Genetic: GS010
GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 will be administrated via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) as a single baseline intravitreal injection.
Drug: Placebo
The placebo is a BSS, sterile, apyrogenic solution and used for ocular surgery. The placebo will be administered via intravitreal injection in a volume of 90 μL.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Main Selection Criteria:

  • Age 15 years or older on the date of signed informed consent.
  • Clinically manifested vision loss due to ND4 LHON, to any extent, in at least one eye.
  • Vision loss duration of ≤ 365 days (i.e. ≤ 1 year) in each affected eye at Inclusion Visit (Visit 2).

Main Non-Selection Criteria:

  • Contraindication to intravitreal injection in any eye.
  • Subjects refusing to discontinue idebenone.
  • Previous vitrectomy in either eye.
  • Narrow angle in any eye contra-indicating pupillary dilation.
  • 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.
  • History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation.

Main Inclusion Criteria:

  • Vision loss duration of ≤ 365 days (i.e. ≤ 1 year) in each affected eye at Inclusion Visit (Visit 2).
  • Each eye of the subject must maintain at least Hand Motion (HM) visual acuity, as defined by the study's SOP for visual acuity testing.
  • 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.

Main Exclusion Criteria:

  • Light Perception (LP) or No Light Perception (NLP) visual acuity in any eye, as defined by the study's standard operating procedure (SOP) for visual acuity testing.
  • Presence of active infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye.
  • Presence of alcoholism, alcohol dependence, or alcohol or drug abuse (excluding nicotine).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03293524


Contacts
Contact: Mohamed Genead, MD +1 617 455 5077 mgenead@gensight-biologics.com
Contact: Sonia Valero, PharmD +33(0)1 85 76 28 18 svalero@gensight-biologics.com

Sponsors and Collaborators
GenSight Biologics
  More Information

Additional Information:
Responsible Party: GenSight Biologics
ClinicalTrials.gov Identifier: NCT03293524     History of Changes
Other Study ID Numbers: GS-LHON-CLIN-05
2017-002187-40 ( EudraCT Number )
First Submitted: September 19, 2017
First Posted: September 26, 2017
Last Update Posted: September 26, 2017
Last Verified: September 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GenSight Biologics:
Heredity Optic Atrophy
Leber Hereditary Optic Atrophy
Leber Hereditary Optic Neuropathy
LHON
Eye Diseases
Hereditary Eye Diseases
Inherited retinal dystrophies or degeneration
Inborn Genetic Disease
Gene Therapy
Intravitreal Injections
Mitochondrial Disease
AAV2 Vectors
Nervous System Diseases
Neurodegenerative Disease
Heredodegenerative Disorders of the Nervous System
Atrophy
Pathological Conditions, Anatomical
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs

Additional relevant MeSH terms:
Atrophy
Optic Nerve Diseases
Optic Atrophy, Hereditary, Leber
Pathological Conditions, Anatomical
Cranial Nerve Diseases
Nervous System Diseases
Eye Diseases
Optic Atrophies, Hereditary
Optic Atrophy
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Eye Diseases, Hereditary
Genetic Diseases, Inborn
Mitochondrial Diseases
Metabolic Diseases
Central Nervous System Depressants
Physiological Effects of Drugs