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

项目总结/摘要 视网膜色素变性（RP），最常见的遗传性视网膜变性，导致严重的视觉 残疾，没有有效的治疗方法。它是由大量基因中的一个突变引起的 导致视杆细胞退化而保留视锥细胞。燃料棒的损失， 95%的细胞在视网膜外层，导致高水平的氧引起氧化应激，这是一个 锥状光感受器逐渐退化的主要原因。视锥细胞退化导致逐渐 视野缩小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），促进视锥细胞的存活和功能， Rp.一项在30名RP患者中测试口服NAC的临床试验显示出良好的安全性， 剂量为1800 mg bid，导致眼内水平良好，并导致圆锥体略有改善 在6个月的治疗期内发挥作用。这导致了一种假设，即长期管理 NAC可促进RP患者的视锥细胞存活，预防严重视力残疾。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，旨在检验 假说.在光谱域光学相干层析成像上测量的椭球区（EZ）宽度 通过中央凹的扫描对应于具有完整的内外段的剩余视锥 是视锥细胞存活的生物标志物。大约438名RP患者，EZ宽度在1500和 8000 µm将以2：1的比例随机分配至1800 mg NAC bid或安慰剂组。主要疗效 目的是确定基线和第45个月（M）之间EZ宽度的累积损失是否 与安慰剂组相比，治疗组受试者的眼睛中显著更少。 次要疗效目的是确定基线和M45之间的平均 黄斑敏感度（通过微视野计测量）或最佳矫正视力被NAC降低 治疗一种新的探索性结果将利用自适应光学扫描光检眼镜， 其允许以单细胞分辨率对锥体镶嵌体进行非侵入性成像，以确定是否 在基线和M45之间，锥密度、间距、规则性和反射率的负变化是 与安慰剂组相比，干预组减少了。所有参与者都将拥有全基因组 测序，这将允许药物基因组学分析。长期NAC的安全性和耐受性 治疗将被仔细评估。这项临床试验有可能确定一种新的非侵入性， 预防RP患者严重视力残疾的口服治疗，无论病因如何 突变，从而解决重大未满足的医疗需求。此外，它将提供最明确的 一项关于氧化损伤是否在RP患者的视锥细胞变性中起主要作用的试验尚未进行 并确定它是否是新治疗开发的有效治疗靶点。

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.