Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year

Study Overview
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Brief Summary
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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.

Detailed Description
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GS-LHON-CLIN-05 is a Phase III, global, multi-center randomized, double-masked for the primary analysis, placebo-controlled, clinical study. As LHON is a neurodegenerative disease, the goal is to administer GS010 as soon as possible upon confirmation of the LHON diagnosis and the causative mutation.

Official Title
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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

Conditions
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Leber Hereditary Optic Neuropathy

Intervention / Treatment
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* Genetic: GS010
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 1<br>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<br>* 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.<br>* Other names: Lenadogene nolparvovec;|
| Placebo Comparator: Treatment Arm 2<br>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<br>* 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.<br>* Other names: Lenadogene nolparvovec;Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year | The primary efficacy endpoint will be the change from baseline (Visit 2) BCVA reported with LogMAR at 1.5 years 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 to represent BCVA. | at 1.5 Year post baseline treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years | Change from baseline in LogMAR BCVA at each timepoint of the follow-up period and at 2 years post-treatment. | at 1.5-Year and 2-Years post baseline treatment | 
| Responder Analysis | Response status at each timepoint of the follow-up period and at 2 years post-treatment. Definitions of responder eyes include: Eyes whose LogMAR BCVA improves (i.e. decreases) by ≥ 0.3 LogMAR (equivalent to a gain of ≥ 15 ETDRS letters) compared to baseline. Eyes whose LogMAR BCVA does not increase (i.e. worsen) by ≥ 0.3 LogMAR (equivalent to eyes that lose ≤ 15 ETDRS letters) compared to baseline. Eyes whose LogMAR visual acuity is < 1.0 (i.e. better than LogMAR 1.0, equivalent to better than Snellen acuity of 20/200). | at 1.5-Year and 2-Years post baseline treatment | 
| Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter | Parameters measured with SD-OCT over time and at 1.5 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 | at 1.5-Year and 2-Years post baseline treatment | 
| Humphrey Visual Field (HVF) parameter | Parameters measured with HVF 30-2 over time and at 1.5 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 | at 1.5-Year and 2-Years post baseline treatment | 
| Pelli Robson Low Vision Contrast Sensitivity parameter | Parameters measured with Pelli Robson Low Vision Contrast Sensitivity over time and at 1.5 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 | at 1.5-Year and 2-Years post baseline treatment | 
| Quality of Life: Visual Functioning Questionnaire-25 | Visual Functioning Questionnaire-25 at 1.5 and 2-years post-treatment | at 1.5-Year and 2-Years post baseline treatment | 
| Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire | 36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment. | at 1.5-Year and 2-Years post baseline treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Therapy, 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, 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