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.

尽管过去20年来血糖和血压控制有所改善， “肾保护”药物如肾素-血管紧张素系统阻滞剂，终末期肾病的发病率 1型糖尿病（T1 D）的终末期肾病（ESRD）没有下降。补充这些干预措施的新疗法是 迫切需要。前瞻性研究的越来越多的证据表明， 酸是慢性肾脏疾病风险增加的一个强有力的独立预测因子， T1 D患者的肾功能丧失。研究降尿酸是否能降低肾小球滤过率， 针对T1 D患者的滤过率（GFR）损失，我们建立了PERL（预防T1 D患者的早期肾功能丧失）。 糖尿病）联盟，包括来自乔斯林糖尿病中心，明尼苏达大学， 科罗拉多、多伦多和密歇根、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资助R 03 DK 094484的支持下，该联盟设计了一个 一项为期3年的多中心、双盲、安慰剂对照、随机临床试验， 目的是评价降尿酸药物别嘌呤醇与安慰剂相比， 减少T1 D受试者的肾功能丧失。该试验针对T1 D患者， 微量白蛋白尿或中度大量白蛋白尿和血清尿酸水平e 4.5 mg/dl，因为这些是 GFR快速下降的风险非常高，并且可能从尿酸减少中获益最多的患者 酸水平。要求研究受试者的GFR在45 - 99 ml/min/1.73 m2之间，符合 目的是在临床DN过程中相对早期进行干预，而不是在结构性DN发生的后期阶段进行干预。 这些变化是非常严重的，而且很大一部分肾功能已经丧失。主 研究的终点将是2个月治疗结束时的GFR（通过碘海醇血浆消失测量） 3年干预后的洗脱期。各种脱落和非脱落情况下的样本量计算 依从性情景表明，每个治疗组240例受试者将提供至少80%的把握度， 检测别嘌呤醇组与安慰剂组相比GFR下降的有临床意义且可实现的降低。 我们最近得到了青少年糖尿病研究基金会（JDRF）的资助， 在两个中心进行的研究，每组30名受试者，以试验PERL的所有临床研究程序和数据流 和管理职能。基于这一经验，并在赠款R34 DK 097808的支持下，我们 现在，我们正在建立关键试验的基础设施，以便我们准备开始招募患者， 一旦这个项目得到资金。如果我们证明别嘌呤醇可以阻止或减缓T1 D患者的GFR下降， 受试者，我们将提供一种安全廉价的干预措施，以预防或延迟T1 D肾衰竭， 在肾损伤的最早临床可检测阶段应用。很难夸大它的重要性 无论从公共卫生角度还是从糖尿病患者的角度来看，这一发现都是正确的。