Trial of Pirfenidone to Prevent Progression of Chronic Kidney Disease (TOPÃÂâÃÂÃÂÃÂÃÂCKD)

吡非尼酮预防慢性肾病进展的试验

• 批准号: 10687662
• 负责人: Joachim H Ix
• 金额: $ 20万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687662
• 关键词: Adult; Affect; Age; Age-Years; Angiotensin-Converting Enzyme Inhibitors; Biological Markers; Biopsy; Chronic Kidney Failure; Clinical Trials; Creatinine; Data; Development; Diabetes Mellitus; Diffusion Magnetic Resonance Imaging; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Event; Fibrosis; Glomerular Filtration Rate; Iohexol; Kidney; Kidney Diseases; Lead; Liquid substance; Lung diseases; Measures; Methods; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Pirfenidone; Placebo Control; Placebos; Population; Prevention; Randomized Clinical Trials; Renal function; Safety; Serum; Severities; Site; Testing; Tissues; United States Food and Drug Administration; Urine; Vital capacity; experience; global health; glycemic control; idiopathic pulmonary fibrosis; kidney biopsy; kidney fibrosis; mortality risk; phase 3 study; phase III trial; post gamma-globulins; prevent; public health relevance; side effect

Project Summary/Abstract Chronic kidney disease (CKD) is a global health problem, affecting more than half of adults over 70 years of age. Other than glycemic control in diabetes and use of angiotensin converting enzyme inhibitors, few specific therapies are available. Fibrosis is a dominant factor in the development and progression of nearly all forms of kidney diseases. Our group has led the development of non-invasive tests to evaluate the severity of fibrosis, in the absence of an invasive kidney biopsy, and we have experience leading clinical trials in CKD. Pirfenidone (Esbriet ®) is a first-in-class anti-fibrotic drug that is approved by the Food and Drug Administration (FDA) for treatment of idiopathic pulmonary fibrosis (IPF). In large-scale, phase 3 studies in IPF patients, pirfenidone showed substantial improvement in forced vital capacity, and significantly reduced the risk of death by 48%. Pharmacokinetic studies and pilot studies show that pirfenidone is safe in the setting of CKD, and have defined the dose of pirfenidone to maximize benefit and minimize side effects in CKD patients. Here, we propose a two-site, double-blind, placebo-controlled, phase 2b trial of pirfenidone 1335 mg/day vs. matched placebo in 160 CKD patients. In our first aim, we will determine the effect of pirfenidone on changes in renal fibrosis measured by diffusion-weighted magnetic resonance imaging (DW-MRI). In our second aim, we will determine the effect of pirfenidone on changes in urine biomarkers that are known to reflect the severity of fibrosis on biopsy, and are predictive of progressive loss of kidney function. Finally, prior anti-fibrotic trials in CKD patients lowered serum creatinine in early phase studies, but failed to prevent CKD progression events in phase 3 trials. The lowering of serum creatinine proved to be due to fluid retention rather than improvements in kidney function. To inform the most appropriate method to assess kidney function in a subsequent large- scale phase 3 trial, our 3rd Aim will determine whether the effect of pirfenidone on glomerular filtration rate (GFR) is similar when using measured glomerular filtration rate (GFR) by iohexol compared with GFR estimates obtained from serum creatinine or cystatin C. In the conduct of this trial, we will also obtain additional information about the safety and tolerability of pirfenidone in CKD. If successful, this study will lead directly to a large-scale, phase 3 trial evaluating pirfenidone for prevention of CKD progression in moderate-to- severe CKD. This project is ideally timed because of the combination of strong preliminary data, the FDA approval and widespread use of pirfenidone for IPF, and the enormous unmet need for new CKD treatments.

项目概要/摘要 慢性肾病 (CKD) 是一个全球性健康问题，影响超过一半的 70 岁以上成年人 除了糖尿病的血糖控制和血管紧张素转换酶抑制剂的使用外，很少有具体的治疗方法。 纤维化是几乎所有形式的疾病发生和进展的主要因素。 我们的团队领导了非侵入性测试的开发，以评估纤维化的严重程度， 在没有进行侵入性肾活检的情况下，我们在 CKD 方面拥有领先的临床试验经验。 (Esbriet ® ) 是一种一流的抗纤维化药物，经美国食品和药物管理局 (FDA) 批准用于 治疗特发性肺纤维化 (IPF) 在针对 IPF 患者的大规模 3 期研究中，吡非尼酮。 用力肺活量显着改善，死亡风险显着降低 48%。 药代动力学研究和初步研究表明，吡非尼酮在 CKD 治疗中是安全的，并已明确 在此，我们提出了一种能够最大限度地提高 CKD 患者获益并最大限度地减少副作用的吡非尼酮剂量。 吡非尼酮 1335 毫克/天与匹配安慰剂的两中心、双盲、安慰剂对照 2b 期试验 我们的第一个目标是确定 160 名 CKD 患者的吡非尼酮对肾纤维化变化的影响。 通过扩散加权磁共振成像 (DW-MRI) 进行测量 在我们的第二个目标中，我们将确定。 吡非尼酮对尿液生物标志物变化的影响，这些生物标志物已知可反映纤维化的严重程度 最后，之前对 CKD 患者进行的抗纤维化试验。 在早期研究中降低血清肌酐，但在第 3 期研究中未能预防 CKD 进展事件 试验证明，血清肌酐的降低是由于液体潴留，而不是肾脏的改善。 为随后的大规模阶段评估肾功能提供最合适的方法。 3 试验，我们的第 3 个目标将确定吡非尼酮对肾小球滤过率 (GFR) 的影响是否相似 当使用碘海醇的肾小球滤过率 (GFR) 进行测量时，与通过以下方法获得的 GFR 估计值进行比较 血清肌酐或胱抑素 C。在进行本试验时，我们还将获得有关 吡非尼酮治疗 CKD 的安全性和耐受性 如果成功，这项研究将直接进入大规模的第 3 阶段。 评估吡非尼酮预防中重度 CKD 进展的试验。 由于强有力的初步数据、FDA 的批准和广泛使用的结合，时机非常理想 吡非尼酮治疗 IPF，以及对新的 CKD 治疗方法的巨大未满足需求。