Phase II Clinical Trial of the Safety and Efficacy if a NOX1/4 Inhibitor in IPF

特发性肺纤维化(IPF)是老年人的一种病态纤维增生性肺部疾病，可导致 进行性呼吸困难和低氧血症。目前对IPF的治疗只有部分有效，而且经常有效 不可接受的副作用。开发一种安全、有效的IPF疗法将是一大进步。 由NADPH氧化酶(NOX)产生的活性氧物种(ROS)在植物生长发育过程中起重要作用。 纤维化的发展。在这个tPPG的第一周期中的研究表明，用一种 小分子药物(GKT137831)可降低肺异常程度， 改善持续性纤维化动物模型的存活率。GKT137831治疗也可降低ROS 在肝、肾和心脏纤维化的其他动物模型中，细胞外基质的产生和减少。 重要的是，GKT137831在其他适应症的早期人体试验中具有良好的安全性。 在这个tPPG的第一周期进行的其他研究表明，O，O‘-Dytyroine，这是一种由ROS诱导的 IPF患者血浆中蛋白质-酪氨酸残基的共价修饰增加18倍 相对于健康对照组。细胞外基质转换也是IPF发病的一个基本过程，并增加 在基质金属蛋白酶的胶原消化循环产物中，包括新表位 C1M，最近被证明可以预测IPF患者的肺部疾病进展。 我们推测，使用NOX1/4抑制剂GKT137831治疗将减轻IPF的氧化损伤 患者，并在此提出一项先导性研究来检验这一假说。 具体目标1的目标是在60名非卧床IPF患者中进行IIB期双盲临床试验 五个主要医疗中心的受试者。受试者将被随机分配到GKT137831或安慰剂，比例为1：1 治疗了六个月。这项试验的主要终点将是对O，O‘-二氢酪氨酸血浆的治疗效果 水平，测量的治疗前，每隔六周。我们假设GKT137831疗法将减少 血浆O，O‘-酪氨酸水平，反映药物诱导的ROS损伤减轻。 特定目标2将确定GKT137831与安慰剂相比的效果。)胶原蛋白降解 血清中产物C1M浓度；b.)用力肺活量；c.)步行六分钟距离；以及d.) 不良事件(AE)发生率。我们假设GKT137831治疗会减少C1M，并有一个可接受的 AE配置文件。临床措施将有助于检测到这一新方法前所未有的好处。 这项高度创新的临床试验可以提供证据表明，选择性抑制NOX是安全和 对IPF患者有益。本研究的结果将有助于确定和建立方法，并提供 促进和证明后续最终试验的合理性，以评估NOX的临床益处 IPF中的抑制剂。这项研究具有转变范式的潜力，将填补现有的几个空白， 最终可以延长许多未来患者的生命。

Idiopathic pulmonary fibrosis (IPF) is a morbid fibroproliferative lung disease of older adults that causes progressive dyspnea and hypoxemia. Current treatments for IPF are only partly efficacious, and often have unacceptable side-effects. Development of a safe, effective IPF therapy would be a major advance. Reactive oxygen species (ROS) generated by NADPH oxidases (NOX) play an important role in the development of fibrosis. Investigations during Cycle 1 of this tPPG showed that inhibition of NOX4 with a small molecule pharmaceutical (GKT137831) decreased the severity of the pulmonary abnormality and improved survival in an animal model of persistent fibrosis. GKT137831 treatment also reduces ROS production and decreases ECM production in other animal models of liver, kidney, and cardiac fibrosis. Importantly, GKT137831 has a good safety profile in early phase human trials for other indications. Other studies conducted during Cycle I of this tPPG showed that o,o’-dytyrosine, which is a ROS-induced covalent modification of protein-tyrosine residues, was increased 18-fold in the plasma of IPF patients relative to healthy controls. ECM turnover is also a fundamental process in IPF pathogenesis, and increases in the circulating products of collagen digestions by matrix metalloproteinases, including the neoepitope C1M, were recently shown to predict lung disease progression in IPF patients. We hypothesize that treatment with the NOX1/4 inhibitor GKT137831 will reduce oxidative injury in IPF patients, and propose here a pilot study to test this hypothesis. The goal of Specific Aim 1 is to conduct a double-blinded Phase IIB clinical trial in 60 ambulatory IPF subjects at five major medical centers. Subjects will be randomized 1:1 to GKT137831 or placebo, and treated for six months. The primary endpoint of this trial will be treatment effects on o,o'-dityrosine plasma levels, measured pretreatment, and at six week intervals. We hypothesize GKT137831 therapy will reduce plasma levels of o,o'-tyrosine, reflecting a drug-induced reduction of ROS injury. Specific Aim 2 will determine effects of GKT137831 compared to placebo, on a.) Collagen degradation product C1M concentrations in sera; b.) Forced vital capacities; c.) Six-minute walk distances; and d.) Adverse event (AE) rates. We hypothesize GKT137831 therapy will decrease C1M, and have an acceptable AE profile. The clinical measures will facilitate detection of an unprecedented benefit of this novel approach. This highly innovative clinical trial could provide evidence that selective NOX inhibition is safe and beneficial in IPF patients. Results of this study will help to confirm and establish methods, and provide the rationale that will facilitate and justify subsequent definitive trials to evaluate the clinical benefits of NOX inhibitors in IPF. This research has the potential to be paradigm-shifting, will fill several existing gaps, and could ultimately extend the lives of many future patients.