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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-002153-11 | EudraCT Number | ||
| NCT02652767 RESCUE | Other Identifier | clin.trial.gov | |
| NCT02652780 REVERSE | Other Identifier | clin.trial.gov |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GS010-treated Eyes | Experimental | Lenadogene nolparvovec Intravitreal ocular unilateral Injection 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®. |
|
| Sham-treated Eyes | Sham Comparator | Sham Intravitreal ocular unilateral Injection 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GS010 | Genetic | Lenadogene nolparvovec Intravitreal ocular unilateral Injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | from year 2 to year 5 post treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Eyes on Chart | Definition: Visual acuity inferior or equal to LogMAR +1.6 at 5 Years post treatment | Year 5 post-treatment |
Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Nancy Newman, MD | Emory University Hospital Atlanta, Georgia, United States, 30322 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Doheny Eye Center UCLA | Pasadena | California | 91105 | United States | ||
| Emory University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39699886 | Derived | Yu-Wai-Man P, Newman NJ, Biousse V, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Degli Esposti S, La Morgia C, Priglinger C, Karanja R, Taiel M, Sahel JA; LHON Study Group. Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy. JAMA Ophthalmol. 2025 Feb 1;143(2):99-108. doi: 10.1001/jamaophthalmol.2024.5375. | |
| 36449262 |
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| ID | Title | Description |
|---|---|---|
| FG000 | All Patient Treated in RECUE and REVERSE Studies | all patients previously treated in RESCUE and REVERSE studies entered in this long term follow up study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Number | eyes | from year 2 to year 5 post treatment | eyes | eyes |
|
from 2 to 5 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Subjects | All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hip fracture | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cataract | Eye disorders | MedDRA (19.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Magali TAIEL Chief Medical Officer | Gensight Biologics | 0762891252 | mtaiel@gensight-biologics.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 17, 2018 | Jul 24, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 30, 2022 | Jul 24, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D029242 | Optic Atrophy, Hereditary, Leber |
| D005128 | Eye Diseases |
| D015785 | Eye Diseases, Hereditary |
| D030342 | Genetic Diseases, Inborn |
| D028361 | Mitochondrial Diseases |
| D009422 | Nervous System Diseases |
| D019636 | Neurodegenerative Diseases |
| ID | Term |
|---|---|
| D015418 | Optic Atrophies, Hereditary |
| D009896 | Optic Atrophy |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
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| ID | Term |
|---|---|
| C005703 | salicylhydroxamic acid |
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intra patient comparaison
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| Sham Intravitreal Injection | Other | Lenadogene nolparvovec Intravitreal ocular unilateral Injection |
|
| 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 | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment |
| Atlanta |
| Georgia |
| 30322 |
| United States |
| Wills Eye Institute | Philadelphia | Pennsylvania | 19107 | United States |
| CHNO Les Quinze Vingts | Paris | 75012 | France |
| LMU Klinikum der Universität München / Friedrich-Baur-Institut | Munich | 80336 | Germany |
| Ospedale Bellaria | Bologna | 40139 | Italy |
| Moorfields Eye Hospital | London | Greater London | EC1V 2PD | United Kingdom |
| Derived |
| Carelli V, Newman NJ, Yu-Wai-Man P, Biousse V, Moster ML, Subramanian PS, Vignal-Clermont C, Wang AG, Donahue SP, Leroy BP, Sergott RC, Klopstock T, Sadun AA, Rebolleda Fernandez G, Chwalisz BK, Banik R, 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; the LHON Study Group. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation. Ophthalmol Ther. 2023 Feb;12(1):401-429. doi: 10.1007/s40123-022-00611-x. Epub 2022 Nov 30. |
| 34108929 | Derived | 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. |
| Death |
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Best Corrected Visual Acuity | Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity scale. | Mean | Standard Deviation | LogMAR |
|
| Sham Treated Eyes |
All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit. |
|
|
| 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 | 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). | Posted | Mean | Standard Deviation | LogMar | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment | eyes | 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 | 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). | Posted | Number | percentage of eye | Nadir to 5 Years post-treatment, Assessed at Baseline in RESCUE and REVERSE studies to year 5 post-treatment | eyes | eyes |
|
|
|
| Other Pre-specified | Eyes on Chart | Definition: Visual acuity inferior or equal to LogMAR +1.6 at 5 Years post treatment | 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). | Posted | Number | percentage of eyes | Year 5 post-treatment | eyes | eyes |
|
|
|
| 2 |
| 62 |
| 8 |
| 62 |
| 19 |
| 62 |
| humerus fracture | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| cardiac arrest | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
|
| ileus | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| lower limb fracture | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| limb injury | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| cerebral haemorrage | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| glioblastoma multiforme | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.0) | Systematic Assessment |
|
| appenditis perforated | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| pneumonia | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.0) | Systematic Assessment |
|
| Gamma-Glutamyltransferase Increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Intraocular Pressure Increased | Eye disorders | MedDRA (19.0) | Systematic Assessment |
|
| Covid-19 | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
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| D020271 |
| Heredodegenerative Disorders, Nervous System |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |