NAC Attack, A Phase-3, Multicenter, Randomized, Placebo-Controlled Trial in Patents with Retinitis Pigmentosa

NAC Attack，针对色素性视网膜炎的 3 期、多中心、随机、安慰剂对照试验

• 批准号: 10593947
• 负责人: Peter A Campochiaro
• 金额: $ 42.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-17 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593947
• 关键词: Acetylcysteine; Address; Affect; Age; Animal Model; Antioxidants; Area; Biological Markers; Blindness; Caring; Cause of Death; Cell Death; Cells; Cessation of life; Clinical Research; Clinical Trials; Clinical Trials Design; Complement; Cone; Consumption; Controlled Clinical Trials; Data; Development; Diabetic Retinopathy; Disease; Dose; Early treatment; Eye; Feasibility Studies; Future; Genes; Genotype; Goals; Grant; Health; Individual; Intervention Trial; Laboratories; Legal patent; Light; Masks; Maximum Tolerated Dose; Measures; Medical; Methodology; Mission; Mutation; NIH Program Announcements; National Eye Institute; Natural History; Ophthalmoscopy; Optical Coherence Tomography; Optics; Oral; Outcome; Outcome Assessment; Outcome Measure; Oxidative Stress; Oxygen; Participant; Pathogenicity; Patient Outcomes Assessments; Patients; Perimetry; Pharmacogenomics; Phase; Phase I Clinical Trials; Placebo Control; Placebos; Play; Population; Protocols documentation; Randomized; Reading; Recording of previous events; Research Personnel; Research Project Grants; Research Proposals; Resolution; Resources; Retina; Retinal Cone; Retinitis Pigmentosa; Rod; Role; Safety; Sample Size; Sampling Studies; Scanning; Site; Smoking Status; Subgroup; Symptoms; Testing; Time; Treatment Efficacy; Vision; Visual; Visual Acuity; Visual Fields; Width; adaptive optics; adaptive optics scanning laser ophthalmoscopy; causal variant; comparative efficacy; constriction; density; disability; effective therapy; efficacy testing; evidence base; experience; fovea centralis; functional outcomes; gene therapy; genome sequencing; genomic data; group intervention; improved; inherited retinal degeneration; macula; meter; mosaic; mouse model; new therapeutic target; non-invasive imaging; novel; oral supplementation; oxidative damage; photoreceptor degeneration; placebo group; prevent; primary outcome; programs; randomized placebo controlled trial; response; retinal rods; sex; therapeutic target; therapy development; tomography; treatment duration; treatment group; whole genome

PROJECT SUMMARY/ABSTRACT Retinitis pigmentosa (RP), the most common inherited retinal degeneration, causes severe visual disability and has no effective treatments. It is caused by mutations in one of a large number of genes that result in rod photoreceptor degeneration while sparing cones. The loss of rods, which constitute 95% of the cells in the outer retina, results in high levels of oxygen causing oxidative stress which is a major contributor to gradual degeneration of cone photoreceptors. Cone degeneration causes gradual constriction of visual fields and eventual blindness. Compelling laboratory data demonstrate that antioxidants, including N-acetylcysteine (NAC), promote cone survival and function in animal models of RP. A clinical trial testing oral NAC in 30 RP patients showed good safety with a maximum tolerated dose of 1800 mg bid, which resulted in good intraocular levels and caused small improvements in cone function over a 6-month treatment period. This has led to the hypothesis that long-term administration of NAC can promote cone survival and prevent severe visual disability in patients with RP. This project is a large multicenter, randomized, double-masked, placebo-controlled clinical trial designed to test that hypothesis. Ellipsoid zone (EZ) width measured on a spectral domain-optical coherent tomography scan through the fovea corresponds to remaining cones with intact inner and outer segments and thus is a biomarker for cone survival. Approximately 438 RP patients with an EZ width between 1500 and 8000 µm will be randomized in a 2:1 ratio to 1800 mg NAC bid or placebo. The primary efficacy objective is to determine if the cumulative loss of EZ width between baseline and month (M) 45 is significantly less in eyes of subjects in the treatment group versus those in the placebo group. Secondary efficacy objectives are to determine if reductions between baseline and M45 in mean macular sensitivity (measured by microperimetry) or best-corrected visual acuity are decreased by NAC treatment. A novel exploratory outcome will utilize adaptive optics scanning light ophthalmoscopy, which allows non-invasive imaging of the cone mosaic with single-cell resolution, to determine if negative changes in cone density, spacing, regularity, and reflectivity between baseline and M45 are reduced in the intervention group versus the placebo group. All participants will have whole genome sequencing which will allow pharmacogenomic analyses. The safety and tolerability of long-term NAC treatment will be carefully assessed. This clinical trial has the potential to identify a new non-invasive, oral treatment that prevents severe visual disability in patients with RP regardless of the pathogenic mutation, thereby addressing a major unmet medical need. In addition, it will provide the most definitive test yet as to whether oxidative damage plays a major role in cone degeneration in patients with RP and determine if it is a validated therapeutic target for new treatment development.

项目摘要/摘要 视网膜炎色素（RP）是最常见的遗传残留变性，导致严重的视觉 残疾，没有有效的治疗方法。它是由大量基因之一突变引起的 这会导致棒感受器变性，同时保留锥。构成杆的损失 外视网膜中95％的细胞导致高水平的氧气引起氧化应激，这是一个 锥形感受器等级变性的主要贡献者。锥变性导致等级 视野和最终失明的收缩。引人入胜的实验室数据表明 包括N-乙酰半胱氨酸（NAC）在内的抗氧化剂，促进锥体存活和功能 RP。 30例RP患者的临床试验测试口服NAC表现出良好的安全性，最大耐受性 剂量为1800 mg，这导致了良好的眼内水平，并导致锥体的改善很小 在6个月的治疗期内的功能。这导致了以下假设 NAC可以促进RP患者的锥体存活并防止严重的视觉障碍。这个项目 是一项大型多中心，随机，双掩蔽，安慰剂对照的临床试验，旨在测试该试验 假设。椭圆形区域（EZ）宽度在光谱域 - 光学层析成像上测得的宽度 通过中央凹扫描对应于具有完整内部和外部段的剩余锥，因此 是锥生存的生物标志物。大约438例RP患者，EZ宽度在1500和 8000 µm将以2：1的比率与1800 mg NAC竞标或安慰剂随机分配。主要效率 目的是确定基线和月之间EZ宽度的累积损失（M）45是 与安慰剂组的受试者眼睛相比，受试者的眼睛的眼睛要少得多。 次要效率目标是确定平均值中的基线和M45之间的减少是否减少 NAC降低了黄斑敏感性（通过微量工测量）或最校正的视力降低 治疗。一种新颖的探索性结果将利用自适应光学扫描光眼镜扫描， 这允许通过单细胞分辨率对锥体镶嵌物进行非侵入性成像，以确定是否是否 锥密度，间距，规律性和基线和M45之间的反射率的负变化为 与安慰剂组相比，干预组减少了。所有参与者都将拥有整个基因组 测序将允许药物基因组学分析。长期NAC的安全性和耐受性 治疗将仔细评估。该临床试验有可能确定一种新的非侵入性， 口服治疗可防止RP患者的严重视觉残疾，无论致病性如何 突变，从而解决了主要的未满足医疗需求。此外，它将提供最明确的 测试氧化物损伤在RP患者中是否在锥变性中起主要作用 并确定它是否是新治疗开发的经过验证的治疗靶标。