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: 10474709
• 负责人: Joachim H Ix
• 金额: $ 15万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474709
• 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; 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 年龄。除了糖尿病的血糖控制和使用血管紧张素转换酶抑制剂外，很少有具体的方法 可以采用治疗方法。纤维化是几乎所有形式的疾病发生和进展的主导因素 肾脏疾病。 Our group has led the development of non-invasive tests to evaluate the severity of fibrosis, 在没有进行侵入性肾活检的情况下，我们拥有领先的 CKD 临床试验经验。 吡非尼酮（Esbriet®）是美国食品药品监督管理局批准的一流抗纤维化药物 （FDA）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， 吡非尼酮显着改善用力肺活量，并显着降低死亡风险 48%。药代动力学研究和初步研究表明吡非尼酮在 CKD 中是安全的，并且 确定了吡非尼酮的剂量，以最大限度地提高 CKD 患者的获益并最大限度地减少副作用。 在这里，我们提出了一项双中心、双盲、安慰剂对照的 2b 期试验，比较吡非尼酮 1335 毫克/天与 1335 毫克/天。 在 160 名 CKD 患者中进行了匹配的安慰剂治疗。在我们的第一个目标中，我们将确定吡非尼酮对变化的影响 通过弥散加权磁共振成像（DW-MRI）测量的肾纤维化。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严重程度 活检显示纤维化，并且预示肾功能进行性丧失。最后，之前的抗纤维化试验 CKD 患者在早期研究中降低了血清肌酐，但未能预防 CKD 进展事件 第三阶段试验。血清肌酐的降低被证明是由于液体潴留而不是改善 在肾功能方面。告知在随后的大型研究中评估肾功能的最合适方法 规模3期试验，我们的第三个目标将确定吡非尼酮是否对肾小球滤过率有影响 使用碘海醇测量的肾小球滤过率 (GFR) 与 GFR 相比，(GFR) 相似 从血清肌酐或胱抑素 C 获得的估计值。在进行本试验时，我们还将获得 有关吡非尼酮治疗 CKD 的安全性和耐受性的更多信息。如果成功的话，这项研究将引领 直接参与一项大规模 3 期试验，评估吡非尼酮预防中度至 CKD 进展的效果 严重的慢性肾病。该项目的时机非常理想，因为结合了强有力的初步数据，FDA 吡非尼酮治疗 IPF 的批准和广泛使用，以及对新型 CKD 治疗方法的巨大未满足需求。