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

项目摘要/摘要 视网膜色素变性是最常见的遗传性视网膜变性，会导致严重的视力问题。 残疾，没有有效的治疗方法。它是由大量基因中的一个基因突变引起的 这会导致杆状感光细胞退化，而保留视锥细胞。棒的损失，这构成了 外视网膜中95%的细胞会产生高水平的氧气，导致氧化应激，这是一种 是视锥感光细胞逐渐退化的主要原因。锥体退变导致渐进性 视野收缩，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)，促进锥体存活和功能的动物模型 反相。30例RP患者口服NAC的临床试验显示安全性良好，最大耐受性 剂量为1800 mg，2次/d，可获得良好的眼内水平，并使锥体略有改善 在6个月的治疗期内发挥作用。这导致了一种假设，即长期给药 NAC能促进视锥细胞存活，预防RP患者的严重视力障碍。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 假设。在光谱域上测量椭球区(EZ)宽度-光学相干层析成像 扫描中心凹对应于剩余的视锥细胞具有完整的内外节段，因此 是锥体存活的生物标记物。大约438名EZ宽度在1500到1500之间的RP患者 8000微米将以2：1的比例随机与1800毫克NAC BID或安慰剂进行比较。初见成效 目的是确定基线和月(M)45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。 次要疗效目标是确定基线和M45之间的平均降幅 NAC会降低黄斑敏感度(用微视野计测量)或最佳矫正视力 治疗。一项新的探索性成果将利用自适应光学扫描光眼底镜， 它允许以单细胞分辨率对锥体马赛克进行非侵入性成像，以确定是否 基线和M45之间的锥体密度、间距、规则性和反射率的负面变化是 干预组与安慰剂组相比减少。所有参与者都将拥有完整的基因组 测序将使药物基因组分析成为可能。长期新城疫的安全性和耐受性 治疗将得到仔细评估。这项临床试验有可能发现一种新的非侵入性、 无论致病原因如何，口服治疗可预防RP患者严重视力障碍 突变，从而解决了一个主要的未得到满足的医疗需求。此外，它将提供最明确的 关于氧化损伤是否在RP患者视锥细胞变性中起主要作用的测试尚未完成 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.