Leber Hereditary Optic Neuropathy
Conditions
Keywords
Leber Hereditary Optic Atrophy, Leber Hereditary Optic Neuropathy, LHON, Eye Diseases, Hereditary Eye Diseases, Inherited retinal dystrophies or degeneration, Gene Therapy, Intravitreal Injections, Mitochondrial Disease, AAV2 Vectors, Hereditary Optic Atrophy
Brief summary
The goal of this clinical trial is to assess the efficacy and safety of GS010 gene therapy - (lenadogene nolparvovec) in subjects with LHON due to the G11778A ND4 mitochondrial mutation with a vision loss up to one year.
Detailed description
The REFLECT study is a Phase 3, international, multi-center, randomized, double-masked, placebo-controlled, clinical trial. The primary objective is to assess the efficacy of intravitreal (IVT) of GS010 compared to IVT of placebo in second-affected/not-yet-affected eyes at 1.5 years post-treatment, by analyzing the change from baseline of the visual acuity in ND4 LHON subjects with vision loss up to one year.
Interventions
GENETICGS010
GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 was administrated via intravitreal injection containing 1.2/1.3E11 vg in 90 μL balanced sterile saline solution (BSSS).
DRUGPlacebo
The placebo is a balanced sterile saline solution (BSSS) used for IVT. The placebo was 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)
Masking description
Study treatments were masked and the allocation to treatment groups was not known to the investigator or other persons involved in the conduct of the study, except the site pharmacies personnel to allow for preparation of investigational products before administration, in cases of emergencies and the data safety monitoring board (DSMB). To ensure that the double-masking design of the study was maintained, GS010 and placebo were identical in appearance and storage conditions.
Intervention model description
Each participant had an eye designated as first-affected eye, and a fellow eye designated as either second-affected eye or not-yet-affected eye at the Screening Visit based on non-equal vision loss duration. In participants reporting simultaneous onset of vision loss in both eyes, the second-affected eye was randomly selected between both eyes. All participants received GS010 in their first-affected eye and were randomized in a 1:1 ratio to receive either GS010 (GS010- GS010 treatment arm) or placebo (GS010-Placebo treatment arm) in the second-affected/not-yet-affected eye.
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 |
|---|---|---|
| Change From Baseline of the Best Corrected Visual Acuity (BCVA) Reported With Log of the Minimal Angle of Resolution (LogMAR) at 1.5 Years Post-treatment, in the Second Affected/Not-yet Affected Eyes | at 1.5 years post-treatment, in the second-affected/not-yet affected eyes | The primary efficacy endpoint was the change from baseline of BCVA reported with LogMAR at 1.5-year post-treatment, in the second-affected/not-yet-affected eyes of ND4 LHON patients with vision loss up to one year. LogMAR BCVA was used to represent BCVA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the BCVA Reported With LogMAR at 5 Years Post-treatment, in the Second Affected/Not-yet Affected Eyes | at 5 years post-treatment, in the second-affected/not-yet affected eyes | Change from baseline of BCVA reported with LogMAR at 5 years post-treatment, in the second-affected/not-yet-affected eyes of ND4 LHON patients with vision loss up to one year. LogMAR BCVA was used to represent BCVA. |
| Proportion of Patients Who Switched From Off-chart Eyes to On-chart Eyes at 5 Years Post-treatment | From baseline to 5 years post-treatment | Proportion of patients with both eyes off-chart, defined as those patients unable to read letter on the ETDRS chart, who had at least one eye on-chart, defined as those patients able to read letters on the ETDRS chart (at either 4 meters or 1 meter) at 5 years |
| Responder Analyses - Improvements From Nadir (Gainer Eyes) at 5 Years | From nadir to 5 years post-treatment | Proportion of patients with an improvement of at least -0.3 LogMAR (≥ +15 ETDRS letters) from nadir to year 5 in at least one eye. Nadir was defined for each eye of each subject as the worst value observed from baseline to year 5 |
| Responder Analyses - Clinically Relevant Recovery From Nadir at 5 Years | From nadir to 5 years post-treatment | Proportion of patients with clinically relevant recovery (CRR) from nadir that was defined as patient with a CRR in at least one eye - Patient with at least one eye which was on chart at nadir, and which had an improvement of at least -0.2 LogMAR from nadir, or which was off-chart at nadir but became on-chart |
| Responder Analyses- Clinically Relevant Benefit at 5 Years | From baseline nadir to 5 years post-treatment | Proportion of patients who had clinically relevant stabilization (CRS), defined as eyes with LogMAR BCVA \< 1 at baseline and at 5 years post-treatment or had a clinically relevant recovery (CRR) from nadir. The best response observed in either eye was considered. |
| Quality of Life Questionnaire: VFQ-25 - Composite Score | From baseline to 5 years post-treatment | Change from baseline to 5 years follow up in the Visual Function Questionnaire (VFQ-25) composite score. The VFQ-25 is a patient-reported outcome instrument assessing vision-related quality of life and consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs plus an additional single-item general health rating question. Each item was converted to a 0-100 scale for scoring, where 100 represents the best possible score on the measure and 0 represents the worst. Items within each subscale were averaged to create 12 subscale scores (11 subscales related to vision + 1 subscale related to general health). The vision-related subscale scores (excluding the general health rating question) were then averaged to calculate the composite score. |
Countries
Belgium, France, Italy, Spain, Taiwan, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORNancy Newman, MD
Emory University Hospital Atlanta, Georgia, United States, 30322
PRINCIPAL_INVESTIGATORPatrick Yu-Wai-Man, PhD
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, CB2 0PY, United Kingdom
Participant flow
Recruitment details
108 patients (≥ 15 years old) were screened for eligibility in 13 sites (Belgium, France, Italy, Spain, Taiwan, United Kingdom: 1 site each, and the United States: 7 sites). Of these, 98 were randomized: 48 to treatment Arm 1 (GS010-GS010) and 50 to treatment Arm 2 (GS010-placebo). The remaining 10 participants were screen failures.
Pre-assignment details
108 patients with the G11778A mitochondrial point mutation in the ND4 gene and vision loss of up to 1 year in one or both eyes were screened. Screening failures (10) including patients who did not meet inclusion criteria or met exclusion criteria.
Baseline characteristics
| Characteristic | — |
|---|---|
| Affected eye status Bilateral | 50 Participants |
| Affected eye status Unilateral | 1 Participants |
| Age at onset of the disease | 31.7 years STANDARD_DEVIATION 14.4 |
| Age, Continuous Age at screening | 32.1 years STANDARD_DEVIATION 13.8 |
| Age, Customized ≥ 60 years | 5 participants |
| Age, Customized Between 15 and 18 years | 10 participants |
| Age, Customized Between 18 and 60 years | 41 participants |
| Current alcohol use ≤ 1 drink/day or occasionally : | 27 Participants |
| Current alcohol use > 1 to 2 drinks/day : | 5 Participants |
| Current alcohol use > 2 drinks/day : | 4 Participants |
| Current alcohol use Missing : | 2 Participants |
| Current alcohol use No use : | 13 Participants |
| Durations of disease | 8.3 Months STANDARD_DEVIATION 3.1 |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment East Asia | 15 Participants |
| Region of Enrollment Europe | 27 Participants |
| Region of Enrollment United States | 56 Participants |
| Sex/Gender, Customized Female | 11 participants |
| Sex/Gender, Customized Male | 41 participants |
| Time interval of vision loss between 1st and 2nd-affected eye | 61.9 days STANDARD_DEVIATION 54.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 2 / 49 |
| other Total, other adverse events | 49 / 49 | 49 / 49 |
| serious Total, serious adverse events | 5 / 49 | 6 / 49 |
Outcome results
None listed