Leber Hereditary Optic Neuropathy due to mutations in the mitochondrial NADH Dehydrogenase 4 gene MedDRA version: 16.1 Level: LLT Classification code 10062951 Term: Leber's hereditary optic atrophy neuropathy System Organ Class: 100000004850
Conditions
Interventions
Product Name: Recombinant AAV vector serotype 2 containing the human wild type mitochondrial ND4 gene
Product Code: GS010
Pharmaceutical Form: Suspension for injection
Other descriptive name: RAAV2/2-
Sponsors
GENSIGHT-BIOLOGICS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4 2. Age 18 years old or older at the time of study entry (informed consent signature) 3. Visual acuity = 1/10 of the less functional eye 4. Visual acuity = 3/10 of the less functional eye for the patients of cohort 4 only 5. Sufficient viable retinal ganglion cells (RGC) as determined by optical coherence tomography (OCT): Retinal nerve fiber layer (RNFL) thickness estimation = 80 µm 6. No infection with Human Immunodeficiency Virus (HIV) 7. Negative pregnancy test in women of childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential) 8. Female patients (if childbearing potency) must agree to use an effective methods of birth control during 6 months after the end of treatment 9. Affiliated to or a beneficiary of the French health care system 10. Written informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 22 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 11. Any known allergy or hypersensibility to one of the product used during the trial 12. Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…) 13. Disorder of the ocular humors and of the internal retina involving visual disability 14. Glaucoma 15. Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve 16. Vascular retinal occlusion 17. Narrow angle contra-indicating pupillary dilation 18. Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...) 19. Patients presenting known mutation of other genes implicated in pathological retinal conditions 20. Patients treated by oral corticoids within 14 days prior inclusion at study entry. 21. Patients who had received Idebenone during the 2 months preceding the injection. 22. Participation in any other clinical trial on the eye within 3 months preceding the injection and during the study period 23. Patients who had eye surgery within the last 3 months preceding the inclusion 24. Patients suffering from any systemic illness or showing medically significant abnormal laboratory values at screening 25. Absence of vision on the other contralateral eye 26. Patients affected by pathologies for which the symptoms and/or the associated treatments can alter the visual function, for instance cancers or any pathology of the central nervous system 27. Diabetes patients with symptoms of retinopathy or macula oedema, 28. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study 29. Patient unable or unwilling to comply with the protocol requirements
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Overall incidence of adverse events will be evaluated for each dose level (9xE09 vg, 3xE10 vg or 9xE10 vg), and for the study as a whole. Similarly, the incidence of serious adverse events will be monitored. An interim complete safety analysis will be performed at 24 weeks of follow-up after the injection of the last subject of the 4rd cohort. In addition, a full analysis will be done 48 weeks after the injection of the last included subject.;Timepoint(s) of evaluation of this end point: Interim analysis = 24 weeks Full analysis = 48 weeks;Main Objective: Evaluation of the safety and tolerability of a single intravitreal (IVT) injections of escalating doses of GS010 (9xE09 vg, 3xE10 vg and 9xE10 vg) in patients suffering from Leber Hereditary Optic Neuropathy (LHON) due to mutation G11778A in the mitochondrial NADH Dehydrogenase 4 (ND4) gene;Secondary Objective: Evaluation of the efficacy on visual functional criteria Evaluation of the eye fundus Evaluation of the immunogenicity of GS010 in terms of humoral and cellular immune response | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy by measuring the central visual function as assessed by the visual acuity and visual field 48 weeks after the injection (ETDRS scale, vision test, Computerized visual field) Efficacy on visual criteria overtime, relative to baseline measured by: - Computerized visual field (Humphrey 24.2) to measure visual field (threshold and mean deviation) - Computerized visual field (Octopus) to measure central scotoma - Fundus perimetry measured with micro perimeter - Optical Coherence Tomography (OCT) to measure 360° and each quadrant thickness of peripapillary retinal nerve fiber layer (RNFL) - Visual evoked potential (VEP) to measure latency and amplitude - Pattern Electroretinogram (PERG) to measure peak time and amplitude - Color vision measured by Computer graphic method Evaluation of the eye fundus by OCT and fundus imaging overtime, relative to baseline Cellular and humoral (total and/or neutralizing antibodies) response to AAV2 will be measured;Timepoint(s) of evaluation of this end point: Secondary endpoints will be assessed 48 weeks after the injection of GS010. | — |
Countries
France
Contacts
Public ContactClinical Development
GENSIGHT-BIOLOGICS
Outcome results
None listed