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: 10333382
• 负责人: Peter A Campochiaro
• 金额: $ 34.24万
• 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/10333382
• 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; Mosaicism; 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; Pharmacogenomics; Phase; Phase I Clinical Trials; Placebo Control; Placebos; Play; 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; mouse model; new therapeutic target; non-invasive imaging; novel; oral supplementation; oxidative damage; patient population; 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.

项目概要/摘要 色素性视网膜炎 (RP) 是最常见的遗传性视网膜变性，会导致严重的视力下降 致残，且无有效治疗方法。它是由大量基因之一突变引起的 导致视杆细胞感光细胞退化，同时保留视锥细胞。杆的损失，构成 95% 的细胞位于外视网膜，产生高水平的氧气，导致氧化应激，这是一种 视锥细胞逐渐退化的主要贡献者。视锥细胞退化导致逐渐 视野收缩并最终失明。令人信服的实验室数据表明 抗氧化剂，包括 N-乙酰半胱氨酸 (NAC)，可促进视锥细胞在动物模型中的存活和功能 RP。一项对 30 名 RP 患者进行口服 NAC 测试的临床试验显示出良好的安全性和最大耐受量 剂量为 1800 mg bid，导致良好的眼内水平并导致锥体小幅改善 在 6 个月的治疗期内发挥作用。这导致了长期给药的假设 NAC 可以促进 RP 患者视锥细胞存活并预防严重视力障碍。这个项目 是一项大型多中心、随机、双盲、安慰剂对照临床试验，旨在测试 假设。在谱域光学相干断层扫描上测量的椭球区 (EZ) 宽度 通过中央凹的扫描对应于具有完整内段和外段的剩余锥体，因此 是视锥细胞存活的生物标志物。大约 438 名 RP 患者的 EZ 宽度在 1500 到 1500 之间 8000 µm 将按 2:1 的比例随机分配至 1800 mg NAC bid 或安慰剂。主要功效 目标是确定基线和 45 月 (M) 之间 EZ 宽度的累积损失是否为 与安慰剂组相比，治疗组受试者的眼睛明显减少。 次要功效目标是确定基线和 M45 之间的平均减少是否减少 NAC 会降低黄斑敏感度（通过显微视野检查测量）或最佳矫正视力 治疗。一项新颖的探索性成果将利用自适应光学扫描光检眼镜， 它允许以单细胞分辨率对锥形镶嵌体进行非侵入性成像，以确定是否 基线和 M45 之间锥体密度、间距、规律性和反射率的负变化是 与安慰剂组相比，干预组有所减少。所有参与者都将拥有全基因组 测序将允许药物基因组分析。长期 NAC 的安全性和耐受性 将仔细评估治疗情况。这项临床试验有可能确定一种新的非侵入性、 口服治疗可预防 RP 患者出现严重视力障碍，无论其致病原因如何 突变，从而解决主要的未满足的医疗需求。此外，它将提供最权威的 尚未测试氧化损伤是否在 RP 患者视锥细胞变性中起主要作用 并确定它是否是新疗法开发的有效治疗靶点。