Trial of Pirfenidone to Prevent Progression of Chronic Kidney Disease (TOP-CKD)

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批准的一类抗纤维化药物 (FDA)用于治疗特发性肺纤维化(IPF)。在IPF患者的大规模3期研究中， 吡非尼酮显著改善了用力肺活量，显著降低了死亡风险。 增加了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， 已经确定了吡非尼酮的剂量，以最大限度地增加CKD患者的益处，并将副作用降至最低。 在这里，我们提出了一项双部位、双盲、安慰剂对照的2b期试验，吡非尼酮1335 mg/天与 160例CKD患者配伍安慰剂。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 弥散加权磁共振成像(DW-MRI)测量肾脏纤维化程度。我们的第二个目标是， 我们将确定吡非尼酮对反映病情严重程度的尿液生物标志物变化的影响。 活检显示纤维化，并预示着肾功能的进行性丧失。最后，先前的抗肝纤维化试验 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滞留而不是改善。 在肾功能方面。为在随后的大手术中提供最合适的肾功能评估方法 规模3期试验，我们的第三个目标将确定吡非尼酮对肾小球滤过率的影响 使用碘海醇测得的肾小球滤过率(GFR)与GFR相比，GFR相似 从血清肌酐或胱抑素C获得的估计。在进行这项试验时，我们还将获得 关于慢性肾脏病中吡非尼酮的安全性和耐受性的更多信息。如果成功，这项研究将引领 直接进行大规模3期试验，评估吡非尼酮预防中到重度慢性肾脏病进展的作用 严重的慢性肾脏病。FDA表示，这一项目的最佳时机是因为结合了强有力的初步数据 批准和广泛使用吡非尼酮治疗IPF，以及对CKD新疗法的巨大需求尚未得到满足。

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.