Leber Hereditary Optic Neuropathy
Conditions
Keywords
Heredity Optic Atrophy, Leber Hereditary Optic Atrophy, Leber Hereditary Optic Neuropathy, LHON, Eye Diseases, Hereditary Eye Diseases, Inborn Genetic Disease, Gene Therapy, Intravitreal Injections, Mitochondrial Disease, AAV2 Vectors, Nervous System Diseases, Neurodegenerative Disease, Heredodegenerative Disorders of the Nervous System
Brief summary
The goal of this clinical trial is to assess the long-term safety and efficacy of GS010, a gene therapy, and assess the quality of life in subjects with LHON due to the G11778A ND4 mitochondrial mutation and who were treated in the Rescue or Reverse studies.
Detailed description
Seven investigational centers from the RESCUE and REVERSE studies also participated in the RESTORE study, located in the European union and in the USA. Primary objectives: to assess the long term safety of intravitreal injection up to 5 years of post treatment in subjects who were treated in the RESCUE or REVERSE studies. Secondary objectives: (1) to assess the long-term efficacy of intravitreal GS010 administration up to 5 years post-treatment in subjects who were treated in the RESCUE or REVERSE studies; and (2) to assess the quality of life (QoL) in subjects who were treated with GS010 in the RESCUE or REVERSE studies for up to 5 years post-treatment. Methodology: This was a Phase III prospective long-term follow-up (LTFU) clinical study of subjects previously treated with GS010 and Sham during 2 Phase III studies-RESCUE and REVERSE. The LTFU study followed subjects for an additional 3 years, for a total of 5 years post-injection. The LTFU study included 5 visits at 2, 2.5, 3, 4, and 5 years after the investigational medicinal product (IMP) injection. Safety, efficacy, and QoL variables were assessed during each of the 5 LTFU visits, and descriptive summaries and statistical testing were used for the analysis of the data. This report presents the final analysis of results at Year 5 after treatment administration in RESCUE and REVERSE. Number of analysed subjects: all subjects completing RECUE and REVERSE studies who provided consent for the RESTORE study: 62 subjects.
Interventions
GENETICGS010
Lenadogene nolparvovec Intravitreal ocular unilateral Injection
Lenadogene nolparvovec Intravitreal ocular unilateral Injection
Sponsors
GenSight Biologics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
intra patient comparaison
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject was treated with GS010 IVT injection in either of the RESCUE or REVERSE Phase III clinical studies * Subject of legal consent age has provided informed consent; subjects that are not of legal consent age have undergone their country-approved clinical trial enrollment consent process
Exclusion criteria
* Subject is unwilling or unable to comply with the protocol requirements * Subject has any medical or psychological condition that, in the opinion of the Investigator, may compromise his or her safe participation in the study * Subject is taking or intending to take idebenone during the long-term follow-up study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ocular Adverse Events (AEs) | from year 2 to year 5 post treatment | Number of Eyes with Ocular Adverse events related to study treatment or study procedures as judged by the investigator reported from year 2 to year 5 post treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Acuity | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment | Change from Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment, expressed in LogMAR. On chart visual acuity: Visual acuity inferior or equal to LogMAR +1.6 Off chart visual acuity: Visual acuity superior to LogMar +1.7 Normal vision LogMar: 0 and less than 0 |
| Responder Analysis: Clinically Relevant Recovery | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment | CRR clinically relevant recovery from Nadir defined as i/ for eyes on chart at Nadir, an improvement of at least -0.2 LogMar from Nadir and ii/ for eyes off chart at Nadir eyes that became on chart. Off chart visual acuity expressed in LogMar: more than +1.7 On chart visual acuity expressed in LogMar: less than 1.6 Normal vision LogMar: 0 and less than 0 |
Countries
France, Germany, Italy, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORNancy Newman, MD
Emory University Hospital Atlanta, Georgia, United States, 30322
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenadogene Nolparvovec and Sham All Participants All participants who were enrolled and received both study treatments, GS010 and Sham. All participants in the study received both GS010 and the sham procedure simultaneously. Participants were randomly assigned to receive GS010 in either the right or left eye. The same participants also received the sham procedure in the eye not assigned to GS010, at the same study visit.
GS010: Either the right or left eye received one single dose of GS010 (9E10 vg/eye) via an intravitreal (IVT) injection. The volume of the injected formula was 90 µL. The injection was performed in the vitreous humor under local anesthesia.
Sham procedure: Either the right or left eye (the eye not randomly assigned to GS010) received the sham procedure. One single sham IVT injection was performed by applying pressure to the eye at the location of a typical IVT injection procedure, using the blunt end of a syringe without a needle. | 62 |
| Total | 62 |
Baseline characteristics
| Characteristic | Lenadogene Nolparvovec and Sham All Participants |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 55 Participants |
| Age, Continuous | 35.9 years STANDARD_DEVIATION 15.3 |
| Best Corrected Visual Acuity | 1.40 LogMAR STANDARD_DEVIATION 0.5 |
| Region of Enrollment France | 16 participants |
| Region of Enrollment Germany | 9 participants |
| Region of Enrollment Italy | 1 participants |
| Region of Enrollment United Kingdom | 5 participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 62 |
| other Total, other adverse events | 19 / 62 |
| serious Total, serious adverse events | 8 / 62 |
Outcome results
Primary
Ocular Adverse Events (AEs)
Number of Eyes with Ocular Adverse events related to study treatment or study procedures as judged by the investigator reported from year 2 to year 5 post treatment
Time frame: from year 2 to year 5 post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GS010 Treated Eyes | Ocular Adverse Events (AEs) | 5 eyes |
| Sham Treated Eyes | Ocular Adverse Events (AEs) | 1 eyes |
Secondary
Responder Analysis: Clinically Relevant Recovery
CRR clinically relevant recovery from Nadir defined as i/ for eyes on chart at Nadir, an improvement of at least -0.2 LogMar from Nadir and ii/ for eyes off chart at Nadir eyes that became on chart. Off chart visual acuity expressed in LogMar: more than +1.7 On chart visual acuity expressed in LogMar: less than 1.6 Normal vision LogMar: 0 and less than 0
Time frame: Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment
Population: All efficacy analyses were conducted on the modified intent-to-treat population and additionally in subset populations, as appropriate.The modified intent-to-treat (mITT) population consisted of all subjects who received the IMP in RESCUE or REVERSE Phase III studies, consented to be enrolled in this LTFU study, and provided visual acuity data at Visit 2 (Year 2.5).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GS010 Treated Eyes | Responder Analysis: Clinically Relevant Recovery | 60 percentage of eye |
| Sham Treated Eyes | Responder Analysis: Clinically Relevant Recovery | 66 percentage of eye |
Secondary
Visual Acuity
Change from Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment, expressed in LogMAR. On chart visual acuity: Visual acuity inferior or equal to LogMAR +1.6 Off chart visual acuity: Visual acuity superior to LogMar +1.7 Normal vision LogMar: 0 and less than 0
Time frame: Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment
Population: All efficacy analyses were conducted on the modified intent-to-treat population and additionally in subset populations, as appropriate.The modified intent-to-treat (mITT) population consisted of all subjects who received the IMP in RESCUE or REVERSE Phase III studies, consented to be enrolled in this LTFU study, and provided visual acuity data at Visit 2 (Year 2.5).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GS010 Treated Eyes | Visual Acuity | -0.44 LogMar | Standard Deviation 0.46 |
| Sham Treated Eyes | Visual Acuity | -0.39 LogMar | Standard Deviation 0.36 |
Other Pre-specified
Eyes on Chart
Definition: Visual acuity inferior or equal to LogMAR +1.6 at 5 Years post treatment
Time frame: Year 5 post-treatment
Population: All efficacy analyses were conducted on the modified intent-to-treat population and additionally in subset populations, as appropriate.The modified intent-to-treat (mITT) population consisted of all subjects who received the IMP in RESCUE or REVERSE Phase III studies, consented to be enrolled in this LTFU study, and provided visual acuity data at Visit 2 (Year 2.5).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GS010 Treated Eyes | Eyes on Chart | 76 percentage of eyes |
| Sham Treated Eyes | Eyes on Chart | 79 percentage of eyes |