A Phase 1/2 Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa Associated With NR2E3 and RHO Mutations and Leber Congenital Amaurosis With Mutation(s) in CEP290 Gene
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Ocugen
- 入组人数
- 22
- 试验地点
- 14
- 主要终点
- Study Drug-related adverse events (SDAE)
研究概览
简要总结
This is a Phase 1/2 Study to Assess the Safety and Efficacy of OCU400 in patients with retinitis pigmentosa associated with NR2E3 and RHO mutations and in patients with LCA due to mutation(s) in CEP290 gene (OCU400-101). To document prospective eye pathology in the above subjects Investigators will also conduct a Natural History Study (OCU400-104)i
This is a multicenter study, which will be conducted in two phases and will enroll up to a total of 24 subjects in the OCU400-101 and 100 subjects in the OCU400-104 study.
详细描述
This study will be conducted in two phases enrolling up to 24 subjects. Treated subjects will receive a single subretinal injection of OCU400 in the study eye.
This is a multicenter, open-label, dose-ranging study in two subgroups of subjects with three consecutive cohorts.
A total of 18 adult RP subjects from each of the following subgroups with Biallelic autosomal recessive NR2E3 mutations, autosomal dominant NR2E3 mutations or Autosomal dominant RHO mutations will be selected for dose escalation.
For the Phase I portion of the study, the 3+3 design for sequential dose-escalating cohorts will be used with scheduled 3 dosing levels between 9 and 18 subjects will be used to follow the design.
Up to 3 additional adult LCA patients with CEP290 mutations and at least 1 pediatric LCA subject, will be enrolled in the Phase 2 portion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis and main criteria for inclusion:
- •Subjects meeting all inclusion criteria and none of the
排除标准
- •are eligible for study participation.
- •Inclusion Criteria for Adult RP:
- •Males or females ≥ 18 years of age at the time of informed consent.
- •Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup
- •For the sentinel subject of Cohort 1-3, BCVA ≤ 20/160 in study eye or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
- •For non-sentinel subject, BCVA ≤ 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
- •Able to perform a Multi-Luminance Mobility Testing (MLMT) using study eye, but unable to pass the MLMT at 1 lux, the lowest luminance level tested.
- •Exclusion Criteria for Adult RP:
- •Subject lacks evidence of outer nuclear layer.
- •Considered unsuitable for any reason that may either place the subject at increased risk during participation or interfere with the interpretation of the study outcomes by the Investigator, or the Sponsor after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator.
- •Previous treatment with a gene therapy or cell therapy product.
- •Previous treatment with any investigational drug or device within one year.
- •Any contraindications for subretinal injection.
- •Cataract Surgery within 3 months. YAG capsulotomy within 1 month. Any other intraocular surgery within 6 months.
- •Breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the Treatment Observation Period.
- •Any medical condition with life expectancy < 6 years.
- •Inclusion Criteria for Adult LCA:
- •Males or females at least 18 years of age at the time of informed consent.
- •Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.
- •Best corrected visual acuity (BCVA) equal to or worse than LogMAR +0.7 but equal to or better than LogMAR 3.8 (light perception) in the study eye.
- •Detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (SD-OCT).
- •Exclusion Criteria for Adult LCA:
- •Any symptom of central nervous system involvement/disease that would impact the ability to measure visual function.
- •Considered unsuitable for any reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study safety and efficacy outcomes by the Investigator, after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator.
- •Any contraindications for subretinal injection.
- •Any intraocular surgery within 6 months.
- •Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis).
- •Breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the Treatment Observation Period.
- •Inclusion Criteria for Pediatric RP:
- •Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
- •Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup
- •BCVA ≤ 20/32 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
- •Able to perform a Multi-Luminance Mobility Testing (MLMT) using study eye, but unable to pass the MLMT at 1 lux, the lowest luminance level tested.
- •Exclusion Criteria for Pediatric RP:
- •Subject lacks evidence of outer nuclear layer as determined by spectral-domain optical coherence tomography (SD-OCT).
- •Considered unsuitable for any reason that may either place the subject at increased risk during participation or interfere with the interpretation of the study outcomes by the Investigator, or the Sponsor after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator.
- •Previous treatment with a gene therapy or cell therapy product.
- •Previous treatment with any investigational drug or device within one year.
- •Any contraindications for subretinal injection.
- •Cataract surgery within 3 months. YAG capsulotomy within 1 month. Any other intraocular surgery within 6 months.
- •Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.
- •Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis).
- •Any medical condition with life expectancy < 6 years.
- •Inclusion Criteria for Pediatric LCA:
- •Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
- •Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.
- •Best corrected visual acuity (BCVA) equal to or worse than LogMAR +0.7 but equal to or better than LogMAR 3.8 (light perception) in the study eye.
- •Detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (SD-OCT).
- •Exclusion Criteria for Pediatric LCA:
- •Any symptom of central nervous system involvement/disease that would impact the ability to measure visual function.
- 另有 5 项未显示
研究组 & 干预措施
Cohort 1 (Low Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup
干预措施: OCU400 Low Dose (Drug)
Cohort 3 (High Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup
干预措施: OCU400 High Dose (Drug)
Phase 2 (High and Medium Dose)
Following DSMB confirmation, adult RP subjects with Biallelic autosomal recessive NR2E3 mutations, autosomal dominant NR2E3 mutations, Autosomal dominant RHO mutations will receive a high dose concentration of OCU400 or LCA patients with CEP290 mutation will receive a medium dose concentration of OCU400.
干预措施: OCU400 High Dose (Drug)
Adult Arm
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup will receive a high dose concentration of OCU400 and LCA patients with CEP290 will receive a medium dose concentration of OCU400
干预措施: OCU400 Med Dose (Drug)
Adult Arm
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup will receive a high dose concentration of OCU400 and LCA patients with CEP290 will receive a medium dose concentration of OCU400
干预措施: OCU400 High Dose (Drug)
Second Eye Dosing
Eligible RP participants will be dosed in the untreated fellow eye with a therapeutic dose used in Phase 3 study of OCU400 (1.0x10E11vg/mL in 250 μl ) and will be followed for an additional 48 weeks.
干预措施: OCU400 Second Eye Dosing (Drug)
Cohort 2 (Mid Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup
干预措施: OCU400 Med Dose (Drug)
Pediatric Arm
Pediatric subjects will receive the medium dose concentration
干预措施: OCU400 Med Dose (Drug)
Phase 2 (High and Medium Dose)
Following DSMB confirmation, adult RP subjects with Biallelic autosomal recessive NR2E3 mutations, autosomal dominant NR2E3 mutations, Autosomal dominant RHO mutations will receive a high dose concentration of OCU400 or LCA patients with CEP290 mutation will receive a medium dose concentration of OCU400.
干预措施: OCU400 Med Dose (Drug)
结局指标
主要结局
Study Drug-related adverse events (SDAE)
时间窗: 1 year
Counts, frequencies and percentages of SDAEs. SDAE is a primary adverse event of interest and defined as AEs and SAEs that are direct subjects to the Study Drug only.
Serious adverse events (SAEs)
时间窗: 1 year
Counts, frequencies and percentages of SAEs including Resulted in Death, Life-threatening, Hospitalization, Disabling/incapacitating, Congenital anomaly or birth defect and medically significant AEs ( AE that did not meet any of the above criteria but could have jeopardized the subject and might have required medical or surgical intervention to prevent one of the outcomes listed above).
Treatment-Emergent adverse events (TEAEs)
时间窗: 1 year
Counts, frequencies and percentages TEAEs. TEAEs are defined as an event that was not present prior to administration of the dose of study drug and present after the dose, or if it represents the exacerbation of an event that was present prior to the dose.
Study Drug-related adverse events (SDAE)
时间窗: 1 year
Counts, frequencies and percentages of SDAEs. SDAE is a primary adverse event of interest and defined as AEs and SAEs that are direct subjects to the Study Drug only.
次要结局
- Best-corrected visual acuity (BCVA)(1 year (Changes from baseline))
- Low-luminance visual acuity (LLVA)(1 year (Changes from baseline))
- Slit-lamp biomicroscopy(1 year (Changes from baseline))
- Intraocular pressure (IOP)(1 year (Changes from baseline))
- anti-AAV5 (anti Adeno-associated virus type 5)(1 year)
- Indirect ophthalmoscopy(1 year (Changes from baseline))
- T-cell response(1 year)
- anti-hNR2E3 antibodies (hNR2E3 gene)(1 year)