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

NOX1/4抑制剂治疗IPF的安全性和有效性的II期临床试验

• 批准号: 10218251
• 负责人: STEVEN R DUNCAN
• 金额: $ 52.12万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218251
• 关键词: Adverse event; Animal Model; Biological Markers; Clinical; Clinical Trials; Collagen; Data; Detection; Development; Diabetic Nephropathy; Digestion; Disease; Disease Progression; Double-Blind Method; Dyspnea; Effectiveness; Elderly; Enzyme-Linked Immunosorbent Assay; Enzymes; Extracellular Matrix; Fibrosis; Frequencies; Future; Gelatinase A; Genetic; Goals; Heart; Human; Hypoxemia; Injury; Investigation; Investigational Therapies; Kidney; Lead; Liver Fibrosis; Lung; Lung diseases; Malignant Neoplasms; Mass Spectrum Analysis; Matrix Metalloproteinases; Measures; Mediating; Medical; Medical center; Methods; Mus; Myofibroblast; NADPH Oxidase; NADPH Oxidase 1; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phase II Clinical Trials; Pilot Projects; Placebos; Plasma; Play; Post-Translational Protein Processing; Process; Production; Prognosis; Pulmonary Fibrosis; Randomized; Reactive Oxygen Species; Reporting; Research; Research Personnel; Role; Safety; Seminal; Severities; Surrogate Markers; Testing; Therapeutic; Therapeutic Agents; Translations; Tyrosine; Vital capacity; Walking; coronary fibrosis; design; dityrosine; idiopathic pulmonary fibrosis; improved; inhibitor/antagonist; innovation; kidney fibrosis; mortality; neoantigens; novel; novel strategies; older patient; oxidative damage; phase 1 study; phase III trial; power analysis; primary endpoint; secondary endpoint; side effect; small molecule; small molecule inhibitor; therapeutic target; treatment duration; treatment effect

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.

特发性肺纤维化（IPF）是一种老年人的病态纤维增生性肺病， 进行性呼吸困难和低氧血症。目前IPF的治疗仅部分有效，并且通常具有 无法接受的副作用开发安全、有效的IPF治疗将是一项重大进展。 由NADPH氧化酶（NOX）产生的活性氧（ROS）在细胞凋亡中起重要作用。 纤维化的发展。在该tPPG的第1周期期间的研究显示， 小分子药物（GKT 137831）降低了肺部异常的严重程度， 在持续性纤维化的动物模型中提高存活率。GKT 137831处理也减少ROS 在肝、肾和心脏纤维化的其他动物模型中，ECM的产生和减少ECM的产生。 重要的是，GKT 137831在其他适应症的早期人体试验中具有良好的安全性特征。 在该tPPG的周期I期间进行的其他研究表明，作为ROS诱导的酪氨酸激酶的o，o '-dytyrosine， 蛋白酪氨酸残基的共价修饰，在IPF患者血浆中增加18倍 相对于健康对照。ECM更新也是IPF发病机制中的基本过程，并且增加了 在基质金属蛋白酶降解胶原蛋白的循环产物中，包括新表位 C1 M最近显示可预测IPF患者的肺部疾病进展。 我们假设用NOX 1/4抑制剂GKT 137831治疗将减少IPF的氧化损伤 患者，并在这里提出一个试点研究来测试这一假设。 具体目标1的目标是在60例非卧床IPF患者中进行一项双盲IIB期临床试验 五大医疗中心的研究对象受试者将以1：1的比例随机分配至GKT 137831组或安慰剂组， 治疗了六个月。本试验的主要终点将是对o，o '-二酪氨酸血浆的治疗效果 水平，测量治疗前和六周的间隔。我们假设GKT 137831治疗将减少 o，o ′-酪氨酸的血浆水平，反映了药物诱导的ROS损伤的减少。 具体目标2将确定GKT 137831与安慰剂相比对a.）胶原降解 血清中的产物C1 M浓度; B.）强迫肺活量; c.）6分钟步行距离;和d.） 不良事件（AE）发生率。我们假设GKT 137831治疗将降低C1 M，并具有可接受的 AE特征。临床措施将有助于检测这种新方法的前所未有的益处。 这项高度创新的临床试验可以提供证据证明选择性NOX抑制是安全的， 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 将促进和证明后续确定性试验以评估NOX临床获益的依据 IPF中的抑制剂。这项研究有可能改变范式，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。