Leber Hereditary Optic Neuropathy
Conditions
Keywords
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
Brief summary
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
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.
Interventions
GENETICGS010
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.
DRUGPlacebo
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.
Sponsors
GenSight Biologics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year | at 1.5 Year post baseline treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years | at 1.5-Year and 2-Years post baseline treatment | Change from baseline in LogMAR BCVA at each timepoint of the follow-up period and at 2 years post-treatment. |
| Responder Analysis | at 1.5-Year and 2-Years post baseline treatment | Response status at each timepoint of the follow-up period and at 2 years post-treatment. 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 eyes 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 | at 1.5-Year and 2-Years post baseline treatment | 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 |
| Humphrey Visual Field (HVF) parameter | at 1.5-Year and 2-Years post baseline treatment | 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 |
| Pelli Robson Low Vision Contrast Sensitivity parameter | at 1.5-Year and 2-Years post baseline treatment | 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 |
| Quality of Life: Visual Functioning Questionnaire-25 | at 1.5-Year and 2-Years post baseline treatment | Visual Functioning Questionnaire-25 at 1.5 and 2-years post-treatment |
| Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire | at 1.5-Year and 2-Years post baseline treatment | 36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Electrocardiograms | At 2-Years post baseline treatment | Results of Electrocardiograms (ECGs) |
| Laboratory results | At 2-Years post baseline treatment | Results of laboratory tests from blood collection |
| Immune response evaluations | 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 | up to 4 weeks post-treatment | Results of bio-dissemination testing up to 4-weeks post-treatment |
| Physical examinations | At 2-Years post baseline treatment | Results of physical examinations |
| Adverse events (AEs) and serious adverse events (SAEs) | 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. |
Countries
Belgium, France, Italy, Spain, Taiwan, United Kingdom, United States
Outcome results
None listed