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

基本信息

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
项目类别：
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

项目摘要

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 年在血糖和血压控制方面取得了进步，并且引入了 “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 (T1D) 中的终末期肾病 (ESRD) 并未下降。补充这些干预措施的新疗法是急需。前瞻性研究中越来越多的证据表明，血清尿酸中度升高酸是慢性肾病风险增加和肾病发病率增加的强有力的独立预测因素 T1D 患者肾功能丧失。研究降低尿酸是否可以减少肾小球 T1D 滤过率 (GFR) 损失，我们建立了 PERL（预防早期肾功能损失）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 丹麦糖尿病中心。在 NIH 拨款 R03 DK094484 的支持下，该联盟设计了一个为期三年、多中心、双盲、安慰剂对照、随机临床试验目的是评估降尿酸药物别嘌呤醇与安慰剂相比的疗效减少 T1D 患者肾功能丧失。该试验针对患有以下疾病的 T1D 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，因为这些是肾小球滤过率快速下降的风险非常高且可能从尿酸降低中获益最多的患者酸水平。研究受试者的 GFR 必须在 45 至 99 ml/min/1.73 m2 之间，与目标是在临床 DN 病程中相对早期进行干预，而不是在结构性病变的后期阶段进行干预。变化已经很严重了，很大一部分肾功能已经丧失。初级研究的终点是 2 个月结束时的 GFR（通过碘海醇血浆消失来测量） 3年干预后的清除期。各种dropout和non-的样本量计算坚持情景表明，每个治疗组中的 240 名受试者将提供至少 80% 的力量检测别嘌呤醇组与安慰剂组相比，GFR 下降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，进行了一项小型试点在两个中心每组 30 名受试者进行研究，以试点所有 PERL 的临床研究程序和数据流和管理功能。基于这一经验并在 R34 DK097808 拨款的支持下，我们现在正在为关键试验建立基础设施，以便我们准备好开始招募患者该项目一旦获得资助。如果我们证明别嘌呤醇可以阻止或减缓 T1D 的 GFR 下降受试者，我们将提供安全且廉价的干预措施来预防或延缓 T1D 肾衰竭，这可以在临床可检测的肾损伤的最早阶段应用。很难夸大其重要性这一发现无论从公共卫生还是糖尿病患者的角度来看都是如此。