The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in patients with LHON due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year.
Name: GS010
Description: Both eyes of each subject will receive standard antiseptic preparation, administration of topical local ocular anesthetic agents and will undergo pupillary dilation. Administration of an intra-ocular pressure lowering agent will precede treatment for every subject. GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Subjects will receive a single dose of GS010 in one of their randomly selected eyes, via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) plus 0.001% Pluronic F68®.Type: GeneticGS010-treated Eyes
Name: Sham Intravitreal Injection
Description: Both eyes of each subject will receive standard antiseptic preparation, administration of topical local ocular anesthetic agents and will undergo pupillary dilation. Administration of an intra-ocular pressure lowering agent will precede treatment for every subject. Sham-treated Eyes: One eye of each subject will undergo sham injection. Sham Intravitreal injection will be performed by applying pressure to the eye at the location of a typical intravitreal injection procedure using the blunt end of a syringe without a needle.Type: DeviceSham-treated Eyes
Description: The primary endpoint will be the ETDRS visual acuity (quantitative score) at Week 48 after intravitreal 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.
Measure: ETDRS visual acuity, utilizing derived LogMAR acuity Time: 48 weeks after GS010/sham injectionDescription: ETDRS visual acuity (quantitative score) over the follow-up period and at Week 96 after intravitreal injection. Change from baseline of the LogMAR scores will be used for statistical analysis purposes.
Measure: ETDRS visual acuity, utilizing derived LogMAR acuity Time: 96 weeks after GS010/sham injectionDescription: Response status to treatment at Week 48 and 96 after intravitreal injection will be determined. 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. The number of GS010-treated eyes that qualify as responders will be compared to the number of sham-treated eyes that qualify as responders.
Measure: Responder Analysis: Improvement from Baseline by 15 ETDRS letters or having Visual Acuity >20/200 at 48 and 96 weeks Time: 48 and 96 weeks after GS010/sham injectionDescription: Measure of parameters of high resolution SD-OCT of the posterior pole and optic nerve at Week 48 and Week 96.Total average and quadrant thickness of the RNFL will be evaluated. The various layers of the retina, including the retinal ganglion cell layer and inner plexiform layer, will be analyzed and the thickness/volume will be evaluated.
Measure: High Resolution Spectral Domain Optical Coherence Tomography to measure the optic nerve retinal nerve fiber layer (RNFL) thickness and the thickness/volume of the retinal layers of the macula Time: 48 and 96 weeks after GS010/sham injectionDescription: 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: Humphrey Visual Field 30-2 Time: 48 and 96 weeks after GS010/sham injectionDescription: Measure of contrast sensitivity with the Pelli-Robson chart at Week 48 and Week 96.
Measure: Pelli-Robson Contrast Sensitivity Time: 48 and 96 weeks after GS010/sham injectionDescription: Measure of color vision with the Farnsworth-Munsell 100 Hue color vision test at Week 48 and Week 96.
Measure: Farnsworth-Munsell Color 100 Hue Vision Test Time: 48 and 96 weeks after GS010/sham injectionDescription: 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.
Measure: Adverse Events and Serious Adverse Events Time: Continuous over 96 week study periodDescription: Results of immune response evaluations: Time course of neutralizing antibodies against AAV2 vector and cellular immune response against AAV2 vector and ND4 protein.
Measure: Immune Responses Time: 96 week study periodDescription: Blood bio-dissemination two weeks after injection of GS010. The presence of AAV2 vector DNA in the blood of subjects will be tested for and quantified utilizing quantitative PCR.
Measure: Blood Bio-dissemination of AAV2 Vector DNA Time: Two weeks post GS010 administrationDescription: The better seeing-eye of each patient will be determined at visit 1, prior to randomization. A pre-determined algorithm of criteria in a hierarchy will be used to determine the better seeing-eye based on vision testing results (e.g. visual acuity, SD-OCT, contrast sensitivity). A minimization method will be employed in the randomization process to ensure, as best as possible, an even distribution of better seeing-eyes to receipt of GS010 and sham. Better-seeing eyes that received GS010 will be compared to better-seeing eyes that received sham. A similar analysis will be done for worse-seeing eyes.
Measure: Better-Seeing Eye Comparison Time: 48 and 96 weeks after GS010/sham injectionDescription: Visual Functioning Questionnaire-25.
Measure: Quality of Life: Visual Functioning Questionnaire-25 Time: 48 and 96 weeks after GS010/sham injectionDescription: 36-Item Short Form Health Survey, version 2 Questionnaire.
Measure: Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire Time: 48 and 96 weeks after GS010/sham injectionAllocation: Randomized
Parallel Assignment
There is one SNP
Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for More Than 6 Months and To 12 Months by LHON Due to the G11778A Mutation in the ND4 Gene. --- G11778A ---
Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in patients with LHON due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year. --- G11778A ---
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. --- G11778A ---