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

项目总结/摘要 慢性肾脏病（CKD）是一个全球性的健康问题，影响超过一半的70岁以上的成年人。 年龄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，很少有特异性 治疗是可行的。纤维化是几乎所有形式的纤维化的发展和进展中的主导因素。 肾脏疾病我们的团队领导了非侵入性测试的发展，以评估纤维化的严重程度， 在没有侵入性肾活检的情况下，我们在CKD的临床试验中有领先的经验。吡非尼酮 （Esbriet ®）是一种一流的抗纤维化药物，其被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IPF患者中进行的大规模III期研究中，吡非尼酮 用力肺活量有实质性改善，死亡风险显著降低48%。 药代动力学研究和初步研究表明，吡非尼酮在CKD背景下是安全的，并已定义 吡非尼酮的剂量，以使CKD患者的获益最大化，副作用最小化。在这里，我们提出一个 一项比较吡非尼酮1335 mg/天与匹配安慰剂的两中心、双盲、安慰剂对照、IIb期试验， 160例CKD患者。在我们的第一个目标中，我们将确定吡非尼酮对肾纤维化变化的影响。 通过弥散加权磁共振成像（DW-MRI）测量。在我们的第二个目标中，我们将确定 吡非尼酮对尿生物标志物变化的影响，已知尿生物标志物可反映纤维化的严重程度， 活组织检查，并且预测肾功能的进行性丧失。最后，既往CKD患者的抗纤维化试验 在早期研究中降低血清肌酐，但在III期研究中未能预防CKD进展事件 审判血清肌酐的降低被证明是由于液体潴留而不是肾脏的改善 功能为在后续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 当使用碘海醇测量的肾小球滤过率（GFR）与 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，这项研究将直接导致大规模的第三阶段， 评价吡非尼酮预防中重度CKD进展的试验。这个项目是 由于强大的初步数据，FDA的批准和广泛使用， 吡非尼酮治疗IPF，以及对新型CKD治疗的巨大未满足需求。

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.