Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE)

Study Overview
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Brief Summary
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The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year.

Official Title
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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

Conditions
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Optic, Atrophy, Hereditary, Leber

Intervention / Treatment
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* Biological: GS010
* Device: Sham Intravitreal Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Selection Criteria: Participants must meet all the following criteria at the Screening Visit (Visit 1) in order to be included into the study. Age 15 years or older. Onset of vision loss based on medically documented history or participants testimony, in both eyes for 181 and ≤365 days in duration. Each eye of the participant maintaining visual ability to allow at least for counting of the examiner's fingers at any distance. Female participants (if of childbearing potential) must agree to use effective methods of birth control up to 6 months after IVT injection and male participants must agree to use condoms for up to 6 months after IVT injection. Ability to obtain adequate pupillary dilation to permit thorough ocular examination and testing. Signed written informed consent. Inclusion Criteria: Participants included in the study must satisfy all the following criteria at the Inclusion Visit (Visit 2). 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 participant's mitochondrial DNA. Review of all selection criteria to ensure continued compliance. Have a negative test for infection with human immunodeficiency virus (HIV). 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). Exclusion Criteria: Non-Selection Criteria: Participants who meet at least one of the following criteria at the Screening Visit (Visit 1) will not be included into the study. Any known allergy or hypersensitivity to GS010 or its constituents. Contraindication to IVT injection. IVT drug delivery to either eye within 30 days prior to the Screening Visit (Visit 1). Previous vitrectomy in either eye. Narrow angle in either eye contra-indicating pupillary dilation. 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. Vision disorders, other than LHON, involving visual disability or with the potential to cause further vision loss during the trial period. Causes of optic neuropathy other than LHON and glaucoma. Participants with known mutations of other genes involved in pathological retinal or optic nerve conditions. Presence of ocular or systemic disease, other than LHON, whose pathology or associated treatments might affect the retina or the optic nerve. 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. Presence of ocular conditions, which in the opinion of the Investigator will prevent good quality SD-OCT imaging from being obtained. Presence, in either eye, of uncontrolled glaucoma, defined as an IOP greater than 25 mmHg, despite maximal medical therapy with intraocular pressure (IOP)-lowering agents. Active ocular inflammation or history of idiopathic or autoimmune-associated uveitis. Participants participating in another clinical trial and receiving an IMP within 90 days prior to the Screening Visit (Visit 1). Previous treatment with an ocular gene therapy product. Participants who have undergone ocular surgery of clinical relevance (per Investigator opinion) within 90 days preceding the Screening Visit (Visit 1). Female participants who are or who intend to breast feed during the trial period. Exclusion Criteria: Participants who meet at least one of the following criteria at the Inclusion Visit (Visit 2) will not be included in the study. Any non-selection criteria which may have appeared after the screening visit. Participants taking idebenone who have not completely discontinued the idebenone at least 7 days prior to Visit 2. If the participant has not discontinued idebenone at least 7 days prior to Visit 2, the visit may be delayed until the 7-day period is complete. Presence, at the time of study inclusion, of infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye. 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 participant's safe participation in the study. 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. Any medical or psychological condition that, in the opinion of the Investigator, may compromise the safe participation of the participant in the study or would preclude compliance with the study protocol or ability of the participant to successfully complete the study. Participants unable or unwilling to comply with the protocol requirements.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS010-treated Eyes<br>Each participant will have one eye randomly selected to receive a single injection of GS010 and the other eye will receive a sham injection. GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Participants 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®. | Biological: GS010<br>* Both eyes of each participant 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 participant. GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Participants 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®.<br>* Other names: rAAV2/2-ND4;|
| Sham Comparator: Sham-treated Eyes<br>Each participant will have one eye randomly selected to receive GS010 and the other eye will receive a sham injection. Eyes receiving sham injection will undergo the same preparatory procedures as eyes receiving GS010 injection, including pupillary dilation, topical anti-infection and topical anesthetic procedures. 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. | Device: Sham Intravitreal Injection<br>* Both eyes of each participant 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 participant. Sham-treated Eyes: One eye of each participant 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48 | Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (LogMAR) score was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 48 score - Baseline score). | Baseline and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96 | Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (LogMAR) score was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 96 score - Baseline score). | Baseline and Week 96 | 
| Number of Eye Responders to Treatment at Week 48 and Week 96 | An eye was determined as a responder to treatment based on 2 different definitions. Definition 1: An eye responder was defined by an improvement of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of at least 15 letters compared to Baseline, or a final visual acuity greater than a Snellen acuity equivalent of 20/200 (a score of at least 1 letter). Definition 2: An eye responder was defined by an improvement of the ETDRS score of at least 20 letters compared to Baseline. | Baseline; Week 48 and Week 96 | 
| Number of Subject Responders to Treatment at Week 48 and Week 96 | A subject responder was defined as a participant whose Early Treatment Diabetic Retinopathy Study (ETDRS) score of the treated eye (that received GS010), was at least 15 letters better than the sham eye, or whose treated eye had a logarithm of the minimal angle of resolution (logMAR) acuity score of at least 0.3 logMAR better than the sham eye. | Week 48 and Week 96 | 
| Change From Baseline in GCL Macular Volume at Week 48 and Week 96 | Ganglion cell layer (GCL) macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering). | Baseline and Week 48; Baseline and Week 96 | 
| Change From Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96 | Retinal nerve fiber layer (RNFL) temporal quadrant thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering). | Baseline and Week 48; Baseline and Week 96 | 
| Change From Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96 | Papillomacular bundle thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering). | Baseline and Week 48; Baseline and Week 96 | 
| Change From Baseline in ETDRS Total Macular Volume at Week 48 and Week 96 | Early Treatment Diabetic Retinopathy Study (ETDRS) total macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering). | Baseline and Week 48; Baseline and Week 96 | 
| Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96 | The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of foveal threshold sensitivities. Foveal threshold sensitivity is measured in decibels (dB), which ranges from 0 dB to 50 dB. A sensitivity threshold of 0 dB indicates not being able to see the most intense perimetric stimulus, while higher dB indicates better/normal foveal vision. A positive change from baseline indicates an improvement of symptoms. | Baseline and Week 48; Baseline and Week 96 | 
| Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96 | The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of the mean deviation (MD) in decibels (dB) of sensitivity. | Baseline, Week 48 and Week 96 | 
| Change From Baseline in Contrast Sensitivity at Week 48 and Week 96 | The assessment of contrast sensitivity was measured using the Pelli-Robson chart. The chart uses letters arranged in groups whose contrast varies from high to low. Participants read the letters, starting with the highest contrast, until they are unable to read 2 or 3 letters in a single group. Each eye is assigned a score based on the contrast of the last group in which 2 or 3 letters were correctly read, ranging from 0 to 2.2 log of contrast sensitivity (LogCS) units. A score of 2.0 LogCS, represents a normal sensitivity contrast, and indicates the eye was able to detect 2 of the 3 letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). Scores less than 2.0 signify poorer contrast sensitivity. Pelli-Robson contrast sensitivity score of less than 1.5 is consistent with visual impairment and a score of less than 1.0 represents in visual disability. A positive change from baseline indicates improvement in symptoms. | Baseline and Week 48; Baseline and Week 96 | 
| Change From Baseline in Color Vision | The assessment of color vision was measured using the Farnsworth-Munsell 100-Hue Color Test. Each of the 4 trays consisted of 21 caps. Participants were asked to sort the randomly arranged caps following the hue order from the first to the last fixed caps. The total error score (TES) was derived by the frequency the caps were misplaced and the severity, or distance of the misplacement. Errors were made whenever caps were misplaced from the correct order. Error scores were calculated according to the distance between any two caps. The error score for each individual cap was the sum of the difference between the number of that cap and the numbers of the cap adjacent to it, minus 2. TES was the total sum of the error scores of the entire set of caps. The best possible score was 0 and there is no defined upper limit to the total error score range. A lower score indicates improved color discrimination ability. A negative change from baseline indicates an improvement in symptoms. | Baseline and Week 48; Baseline and Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leber Hereditary Optic Neuropathy, Leber Hereditary Optic Atrophy, Heredity Optic Atrophy, Eye Diseases, Hereditary Eye Diseases, Inborn Genetic Disease, Genetic Therapy, Intravitreal Injections, Mitochondrial Disease, AAV2 Vectors, Nervous System Diseases, Neurodegenerative Disease, Heredodegenerative Disorders of the Nervous System