Clinical trial NCT02652780: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Optic, Atrophy, Hereditary, Leber
Keywords: 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
Lead sponsor: GenSight Biologics
Sponsor class: INDUSTRY
First posted: 2016-01-12
Enrollment: 37
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

1. Age 15 years or older.
2. Onset of vision loss based on medically documented history or participants testimony, in both eyes for 181 and ≤365 days in duration.
3. Each eye of the participant maintaining visual ability to allow at least for counting of the examiner's fingers at any distance.
4. 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.
5. Ability to obtain adequate pupillary dilation to permit thorough ocular examination and testing.
6. Signed written informed consent.

Inclusion Criteria:

Participants 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 participant's mitochondrial DNA.
2. Review of all selection criteria to ensure continued compliance.
3. Have a negative test for infection with human immunodeficiency virus (HIV).
4. 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.

1. Any known allergy or hypersensitivity to GS010 or its constituents.
2. Contraindication to IVT injection.
3. IVT drug delivery to either eye within 30 days prior to the Screening Visit (Visit 1).
4. Previous vitrectomy in either eye.
5. Narrow angle in either eye contra-indicating pupillary dilation.
6. 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.
7. Vision disorders, other than LHON, involving visual disability or with the potential to cause further vision loss during the trial period.
8. Causes of optic neuropathy other than LHON and glaucoma.
9. Participants with known mutations of other genes involved in pathological retinal or optic nerve conditions.
10. Presence of ocular or systemic disease, other than LHON, whose pathology or associated treatments might affect the retina or the optic nerve.
11. 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.
12. Presence of ocular conditions, which in the opinion of the Investigator will prevent good quality SD-OCT imaging from being obtained.
13. 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.
14. Active ocular inflammation or history of idiopathic or autoimmune-associated uveitis.
15. Participants participating in another clinical trial and receiving an IMP within 90 days prior to the Screening Visit (Visit 1).
16. Previous treatment with an ocular gene therapy product.
17. Participants who have undergone ocular surgery of clinical relevance (per Investigator opinion) within 90 days preceding the Screening Visit (Visit 1).
18. 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.

1. Any non-selection criteria which may have appeared after the screening visit.
2. 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.
3. Presence, at the time of study inclusion, of infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye.
4. 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.
5. 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.
6. 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.
7. Participants unable or unwilling to comply with the protocol requirements.

Primary outcomes:
measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48
timeFrame: Baseline and Week 48
Secondary outcomes:
measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96
timeFrame: Baseline and Week 96
measure: Number of Eye Responders to Treatment at Week 48 and Week 96
timeFrame: Baseline; Week 48 and Week 96
measure: Number of Subject Responders to Treatment at Week 48 and Week 96
timeFrame: Week 48 and Week 96
measure: Change From Baseline in GCL Macular Volume at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Change From Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Change From Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Change From Baseline in ETDRS Total Macular Volume at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96
timeFrame: Baseline, Week 48 and Week 96
measure: Change From Baseline in Contrast Sensitivity at Week 48 and Week 96
timeFrame: Baseline and Week 48; Baseline and Week 96
measure: Change From Baseline in Color Vision
timeFrame: Baseline and Week 48; Baseline and Week 96
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Doheny Eye Center, University of California, Los Angeles
state: California
city: Atlanta
country: United States
facility: Department of Ophthalmology, Emory University School of Medicine
state: Georgia
city: Philadelphia
country: United States
facility: Neuro Ophthalmologic Associates, Wills Eye Hospital, Thomas Jefferson University
state: Pennsylvania
city: Paris
country: France
facility: Centre National Hospitalier d'Ophtalmologie des Quinze-Vingt
city: Munich
country: Germany
facility: Department of Neurology, University of Munich, Friedrich-Baur-Institute
city: Bologna
country: Italy
facility: IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria
city: London
country: United Kingdom
facility: Moorfields Eye Hospital NHS Foundation Trust
Study officials:
affiliation: Moorfields Eye Hospital NHS Foundation Trust
name: Patrick Yu Wai Man, MDPhDFRCOpht
role: PRINCIPAL_INVESTIGATOR
References:
citation: Newman NJ, Yu-Wai-Man P, Carelli V, Biousse V, Moster ML, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Front Neurol. 2021 May 24;12:662838. doi: 10.3389/fneur.2021.662838. eCollection 2021.