Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 98
- 试验地点
- 26
- 主要终点
- Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
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.
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
GS010-Placebo
Patients received single IVT injection of GS010 in their first-affected eye and placebo IVT injection in their second-affected/not-yet-affected eye.
Patients received IVT lenadogene nolparvovec in their first-affected eye (ddPCR dose of 1.2/1.3E11 vg in a volume of 90 μL) and placebo IVT injection (volume of 90 μL) in their second-affected/not-yet-affected eye.
Treatment could be performed either on a single day (1 IVT injection in each eye on Day 0) or on 2 consecutive days (1st IVT injection on Day -1 and 2nd IVT injection on Day 0).
干预措施: Placebo (Drug)
GS010-Placebo
Patients received single IVT injection of GS010 in their first-affected eye and placebo IVT injection in their second-affected/not-yet-affected eye.
Patients received IVT lenadogene nolparvovec in their first-affected eye (ddPCR dose of 1.2/1.3E11 vg in a volume of 90 μL) and placebo IVT injection (volume of 90 μL) in their second-affected/not-yet-affected eye.
Treatment could be performed either on a single day (1 IVT injection in each eye on Day 0) or on 2 consecutive days (1st IVT injection on Day -1 and 2nd IVT injection on Day 0).
干预措施: GS010 (Genetic)
GS010-GS010
Patients received single IVT injection of GS010 in both their first-affected eye and their second-affected/not-yet-affected eye at a droplet digital polymerase chain reaction (ddPCR) dose of 1.2/1.3E11 vg in 90 μL for each eye.
Treatment could be performed either on a single day (1 IVT injection in each eye on Day 0) or on 2 consecutive days (1st IVT injection on Day -1 and 2nd IVT injection on Day 0).
干预措施: GS010 (Genetic)
结局指标
主要结局
Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year
时间窗: at 1.5 Year post baseline treatment
The primary efficacy endpoint will be the change from baseline (Visit 2) BCVA reported with LogMAR at 1.5 years post-treatment in second affected/not yet affected eyes of ND4 LHON subjects with vision loss up to one year. The change from baseline (Visit 2) in second affected/not yet affected eyes receiving GS010 and placebo will be the primary response of interest. LogMAR BCVA will be used to represent BCVA.
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
时间窗: 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.
次要结局
- Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years(at 1.5-Year and 2-Years post baseline treatment)
- Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter(at 1.5-Year and 2-Years post baseline treatment)
- Humphrey Visual Field (HVF) parameter(at 1.5-Year and 2-Years post baseline treatment)
- Pelli Robson Low Vision Contrast Sensitivity parameter(at 1.5-Year and 2-Years post baseline treatment)
- Quality of Life: Visual Functioning Questionnaire-25(at 1.5-Year and 2-Years post baseline treatment)
- Responder Analysis(at 1.5-Year and 2-Years post baseline treatment)
- Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire(at 1.5-Year and 2-Years post baseline treatment)
- 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)
- 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)
- Responder Analyses - Improvements From Nadir (Gainer Eyes) at 5 Years(From nadir to 5 years post-treatment)
- Responder Analyses - Clinically Relevant Recovery From Nadir at 5 Years(From nadir to 5 years post-treatment)
- Responder Analyses- Clinically Relevant Benefit at 5 Years(From baseline nadir to 5 years post-treatment)
- Quality of Life Questionnaire: VFQ-25 - Composite Score(From baseline to 5 years post-treatment)