PERL: A multicenter clinical trial of allopurinol to prevent GFR loss in T1D

PERL：别嘌呤醇预防 T1D 患者 GFR 损失的多中心临床试验

• 批准号: 8644403
• 负责人: Alessandro Doria
• 金额: $ 2431.22万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644403
• 关键词: Adherence; Albuminuria; Allopurinol; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Colorado; Complement; Complications of Diabetes Mellitus; Data; Denmark; Diabetes Mellitus; Diabetic Nephropathy; Double-Blind Method; Dropout; Early Intervention; End stage renal failure; Evidence based intervention; Financial cost; Foundations; Funding; Glomerular Filtration Rate; Goals; Grant; Human; Incidence; Injury; Insulin-Dependent Diabetes Mellitus; Intervention; Iohexol; Kidney; Kidney Failure; Left; Measures; Medicine; Michigan; Microalbuminuria; Minnesota; Morbidity - disease rate; Names; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Plasma; Procedures; Prospective Studies; Protective Agents; Public Health; Randomized Clinical Trials; Recruitment Activity; Renal function; Renin-Angiotensin System; Research; Research Infrastructure; Research Personnel; Residual state; Risk; Sample Size; Serum; Societies; Staging; Steno; Study Subject; Testing; United States National Institutes of Health; Universities; Urate; Uric Acid; arm; base; blood pressure regulation; college; design; experience; glycemic control; high risk; macroalbuminuria; mortality; novel; prevent; public health relevance

Despite improvements in the past 20 years in glycemic and blood pressure control and the introduction of 'renoprotective' drugs such as renin-angiotensin system blockers, the incidence of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel therapies to complement these interventions are urgently needed. Mounting evidence from prospective studies indicates that moderately elevated serum uric acid is a strong, independent predictor of an increased risk of chronic kidney disease and increased rates of loss of kidney function among T1D persons. To study whether uric acid lowering can reduce glomerular filtration rate (GFR) loss in T1D, we have established the PERL (Preventing Early Renal Function Loss in Diabetes) Consortium including investigators from Joslin Diabetes Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, Northwestern University, Albert Einstein College of Medicine, and the Steno Diabetes Center in Denmark. With the support of NIH grant R03 DK094484, the Consortium has designed a three-year, multi-center, double-blind, placebo-controlled, randomized clinical trial with the specific aim of evaluating the efficacy of the urate-lowering drug allopurinol, as compared to placebo, in reducing kidney function loss among subjects with T1D. The trial is targeted to T1D patients with microalbuminuria or moderate macroalbuminuria and serum uric acid levels e 4.5 mg/dl, since these are the patients who are at very high risk of having rapid GFR decline and might benefit most from reductions in uric acid levels. Study subjects will be required to have a GFR between 45 and 99 ml/min/1.73 m2, consistent with the goal of intervening relatively early in the course of clinical DN rather than at later stages when structural changes are far advanced and a very large proportion of kidney function has already been lost. The primary endpoint of the study will be the GFR (as measured by iohexol plasma disappearance) at the end of a 2-month wash-out period after the 3-year intervention. Sample size calculations under various dropout and non- adherence scenarios suggest that 240 subjects in each treatment arm would provide at least 80% power to detect a clinically meaningful and achievable reduction in GFR decline in the allopurinol vs. the placebo group. We have recently been funded by the Juvenile Diabetes Research Foundation (JDRF) to conduct a small pilot study in two centers with 30 subjects/group to pilot all of PERL's clinical research procedures and data flow and management functions. Based on this experience and with the support of grant R34 DK097808, we are now establishing the infrastructure for the pivotal trial so that we will be ready to start recruiting patients as soon as this project is funded. If we demonstrate that allopurinol can halt or slow down GFR decline in T1D subjects, we will provide a safe and inexpensive intervention to prevent or delay kidney failure in T1D that can be applied at the earliest clinically detectable stages of renal injury. It is difficult to overstate how significant this finding would be, both from the perspective of public health and that of persons with diabetes.

尽管在过去20年中在血压和血压控制方面有所改善，并引入了 肾素 - 血管紧张素系统阻滞剂等“肾脏保护性”药物，终末期肾脏疾病的发生率 （ESRD）在1型糖尿病（T1D）中没有下降。补充这些干预措施的新型疗法是 迫切需要。前瞻性研究的越来越多的证据表明，血清尿液中等升高 酸是强大的独立预测指标，是增加慢性肾脏疾病风险的增加和增加的率 T1D人群中肾功能的丧失。研究尿酸降低是否可以减少肾小球 T1D中的过滤率（GFR）损失，我们已经建立了PERL（防止早期肾功能损失 糖尿病联盟，包括来自明尼苏达大学乔斯林糖尿病中心的研究人员， 科罗拉多州，多伦多和密歇根州，西北大学，阿尔伯特·爱因斯坦医学院和Steno 丹麦的糖尿病中心。在NIH Grant R03 DK094484的支持下，该财团设计了 三年，多中心，双盲，安慰剂对照，随机临床试验，特定 与安慰剂相比，在 减少T1D受试者之间的肾功能损失。该试验针对的是T1D患者 微量白蛋白尿或中度大量藻尿症和血清尿酸水平E 4.5 mg/dl，因为这些是 GFR快速下降的风险很高，可能会从减少尿液中受益最高的患者 酸水平。研究对象将必须具有45至99 mL/min/1.73 m2的GFR，与 在临床DN的过程中相对较早而不是在结构性的阶段中相对较早进行介入的目的 变化是相当高的，肾功能已经丢失了很大一部分。主要 研究的终点将是2个月结束时的GFR（通过Iohexol血浆消失测量） 三年干预后的洗涤期。样本量计算在各种辍学和非 - 依从性方案表明，每个治疗臂中的240名受试者至少将提供80％的功率 检测别嘌呤醇与安慰剂组的GFR下降的临床意义和可实现的减少。 最近，我们是由少年糖尿病研究基金会（JDRF）资助的，以进行小型飞行员 在两个受试者/小组的两个中心研究Perl的所有临床研究程序和数据流程 和管理功能。基于这一经验，并在Grant R34 DK097808的支持下，我们是 现在建立关键试验的基础设施，以便我们准备开始招募患者 一旦这个项目获得资助。如果我们证明别嘌呤醇可以停止或减慢T1D的GFR下降 受试者，我们将提供安全且廉价的干预措施，以防止或延迟T1D的肾脏衰竭 以最早的临床可检测到的肾脏损伤阶段应用。很难高估多么重要 从公共卫生的角度和糖尿病患者的角度来看，这一发现都是如此。