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

项目概要/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，已获得美国食品和药物管理局（FDA）的批准。 (FDA)用于治疗特发性肺纤维化（IPF）。在IPF患者的大规模III期研究中， 吡非尼酮显示出用力肺活量的显著改善，并显著降低了死亡风险 48%。药代动力学研究和初步研究表明，吡非尼酮在CKD背景下安全， 已经确定了吡非尼酮的剂量，以使CKD患者的获益最大化，副作用最小化。 在这里，我们提出了一个双中心，双盲，安慰剂对照，2b期试验吡非尼酮1335 mg/天与 在160例CKD患者中使用匹配的安慰剂。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）测量肾纤维化。我们的第二个目标， 我们将确定吡非尼酮对尿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， 在活组织检查中纤维化的发生率，并预示着肾功能的进行性丧失。最后，先前的抗纤维化试验， 在早期研究中，CKD患者血清肌酐降低，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 肾脏功能。为在随后的大型- 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的影响 (GFR)当使用碘海醇测量的肾小球滤过率（GFR）与GFR相比时， 从血清肌酐或胱抑素C获得的估计值。在进行这项试验时，我们还将获得 关于吡非尼酮治疗CKD的安全性和耐受性的其他信息。如果成功，这项研究将导致 直接进入一项评估吡非尼酮预防中度至重度CKD患者CKD进展的大规模III期试验， 重度CKD。这个项目是理想的时间，因为强大的初步数据相结合，FDA 吡非尼酮治疗IPF的批准和广泛使用，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.