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

项目摘要/摘要 慢性肾脏疾病(CKD)是一个全球性的健康问题，70岁以上的成年人中有一半以上受到影响。 年龄。除了糖尿病患者的血糖控制和血管紧张素转换酶抑制剂的使用外，很少有特异性药物 治疗方法是可用的。纤维化是几乎所有形式的骨质疏松症发生和发展的主导因素 肾脏疾病。我们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，我们在慢性肾脏病方面拥有领先的临床试验经验。吡非尼酮 (Esbriet®)是美国食品和药物管理局(FDA)批准的一种一流抗纤维化药物 治疗特发性肺纤维化(IPF)。在IPF患者的大规模3期研究中，吡非尼酮 用力肺活量有显著改善，死亡风险显著降低48%。 药代动力学研究和初步研究表明，吡非尼酮在慢性肾脏病的治疗中是安全的，并已确定 CKD患者最大受益和最小副作用的吡非尼酮剂量。在这里，我们提出一种 每日服用吡非尼酮1335 mg与服用安慰剂对照的双部位双盲安慰剂对照2b期试验 160例慢性肾脏病患者。在我们的第一个目标中，我们将确定吡非尼酮对肾脏纤维化变化的影响。 用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 吡非尼酮对反映肝纤维化严重程度的尿液生物标志物变化的影响 活组织检查，并预测进行性肾功能丧失。最后，先前在慢性肾脏病患者中进行的抗纤维化试验 在早期研究中降低了血清肌酐，但未能阻止第三阶段的CKD进展事件 审判。血清肌酐的降低被证明是由于液体滞留而不是肾脏的改善。 功能。提供在随后的大规模阶段评估肾功能的最合适的方法 3个试验，我们的第三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 使用碘海醇测得的肾小球滤过率(GFR)与下列方法获得的GFR估计值进行比较时 在进行这项试验的过程中，我们还将获得有关 吡非尼酮在慢性肾脏病中的安全性和耐受性。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慢性肾脏病进展的临床研究。这个项目是 由于强劲的初步数据、FDA的批准和广泛使用的 用于IPF的吡非尼酮，以及对CKD新疗法的巨大未得到满足的需求。

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.