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

吡非尼酮预防慢性肾病 (TOP-CKD) 进展的试验

• 批准号: 10700900
• 负责人: Joachim H Ix
• 金额: $ 52.4万
• 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/10700900
• 关键词: Adult; Affect; Age; Age Years; Angiotensin-Converting Enzyme Inhibitors; Biological Markers; Biopsy; Body Composition; Body Fluids; CCL2 gene; Cause of Death; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Trials; Conduct Clinical Trials; Creatinine; Data; Development; Diabetes Mellitus; Diffusion; Diffusion Magnetic Resonance Imaging; Disease Progression; Dose; Double-Blind Method; Dropout; Drug Kinetics; Etiology; Evaluation; Event; Fibrosis; Focal and Segmental Glomerulosclerosis; Formulation; Future; Glomerular Filtration Rate; Heart failure; Image; Investigational Drugs; Iohexol; Kidney; Kidney Diseases; Lead; Liquid substance; Liver; Longterm Follow-up; Lung diseases; Magnetic Resonance Imaging; Measures; Methods; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Phase; Physical Function; Pilot Projects; Pirfenidone; Placebo Control; Placebos; Population; Prevention; Proteins; Public Health; Randomized; Renal function; Risk; Safety; Serum; Severities; Site; Testing; Tissues; United States; United States Food and Drug Administration; Urine; Vital capacity; alpha-1-microglobulin; antifibrotic treatment; arm; capsule; cardiovascular disorder risk; comorbidity; design; diabetic; experience; gastrointestinal; global health; glycemic control; high risk; idiopathic pulmonary fibrosis; improved; kidney biopsy; kidney fibrosis; mortality; mortality risk; novel therapeutics; phase 3 study; phase III trial; pilot trial; post gamma-globulins; prevent; procollagen Type III-N-terminal peptide; public health relevance; randomized, clinical trials; side effect; urinary

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.

项目摘要 /摘要 慢性肾脏病（CKD）是一个全球健康问题，影响了70年以上的成年人中一半以上 年龄。除了糖尿病的血糖控制以及使用血管紧张素转化酶抑制剂的使用，几乎没有特定的特异性 提供疗法。纤维化是几乎所有形式的发展和发展的主要因素 肾脏疾病。我们的小组领导了非侵入性测试的发展，以评估纤维化的严重程度， 在没有侵入性的肾脏活检的情况下，我们在CKD中经验了领先的临床试验。 Pirfenidone（Esbriet®）是一种一流的抗纤维化药物，得到了食品药品监督管理局的批准 （FDA）治疗特发性肺纤维化（IPF）。在大规模的IPF患者中，第3阶段研究， Pirfenidone在强制生命能力方面表现出很大改善，并显着降低了死亡的风险 增长48％。药代动力学研究和试点研究表明，吡啶酮在CKD的环境中是安全的，并且 已经定义了吡非酮的剂量，以最大程度地提高益处并最大程度地减少CKD患者的副作用。 在这里，我们提出了一项两次双盲，安慰剂对照的2B阶段2B试验1335 mg/day vs。 在160名CKD患者中匹配安慰剂。在我们的第一个目标中，我们将确定吡啶酮对变化的影响 在我们的第二个目标中 我们将确定吡非酮对已知反映严重程度的尿液生物标志物变化的影响 活检的纤维化，并预测肾功能的进行性丧失。最后，先前的抗纤维化试验 CKD患者在早期研究中降低了血清肌酐，但未能防止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保留而不是改善 在肾功能中。告知最适合评估肾功能的方法 比例尺3期试验，我们的第三个目标将确定吡啶酮对肾小球滤过率的影响是否 与GFR相比，使用iohexol的测量肾小球过滤率（GFR）时（GFR）相似 从血清肌酐或胱抑素C获得的估计值C.在该试验的进行中，我们还将获得 有关pirfenidone在CKD中的安全性和耐受性的其他信息。如果成功，这项研究将领导 直接进行大规模的3阶段试验，评估吡芬酮用于预防现代至现代的CKD进展 严重的CKD。由于强大的初步数据，FDA的结合，该项目是理想情况下定时的 Pirfenidone用于IPF的批准和宽度使用，以及对新CKD治疗的巨大未满足的需求。