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

描述(申请人提供)：尽管在过去20年中血糖和血压控制有所改善，肾素-血管紧张素系统阻滞剂等肾脏保护药物的引入，但1型糖尿病(T1D)的终末期肾脏疾病(ESRD)的发病率并未下降。迫切需要新的疗法来补充这些干预措施。来自前瞻性研究的越来越多的证据表明，中度升高的血尿酸是T1D患者慢性肾脏疾病风险增加和肾功能损失率增加的一个强有力的独立预测因素。为了研究降低尿酸是否可以减少T1D的肾小球滤过率(GFR)丢失，我们成立了PERL(预防糖尿病早期肾功能丧失)联盟，成员包括来自Joslin糖尿病中心、明尼苏达大学、科罗拉多大学、多伦多大学和密歇根大学以及丹麦Steno糖尿病中心的研究人员。在NIH资助R03 DK094484的支持下，我们设计了一项为期四年的国际多中心、双盲、安慰剂对照、随机临床试验，以评估与安慰剂相比，降低尿酸的药物别嘌醇在减少T1D患者肾功能损失方面的疗效。这项试验将包括总共400名T1D患者，由于蛋白尿增加和血清尿酸相对较高(e4.5 mg/dl)，他们的肾功能仍然只有轻微或中度下降(GFR=45-99毫升/分钟/1.73平方米)，因此GFR丢失的风险很高。研究的主要终点将是4年干预结束时的肾小球滤过率(通过碘海醇血浆消失来衡量)。我们最近得到了青少年糖尿病研究基金会的资助，在两个中心(Joslin和Steno)进行了一项小型试点研究，共有30名受试者/组，这将建立这样一项试验的可行性，并对其所有临床研究程序、数据流和管理进行试点。在R34的支持下，我们打算使用此信息来源和其他信息来源将此临床 通过实现以下具体目标，试行更接近实施：1.编写《操作手册》。2.在所有研究地点获得IRB批准。3.在每个中心制定招聘战略，包括与卫星中心建立关系。4.建立此次国际试验的药品配送中心。5.开发数据管理、质量控制和研究监督的工具和基础设施。6.制定数据和安全监测计划。通过实现这些目标，一旦获得资金，我们将准备开始招募患者参加关键试验。如果我们能够证明别嘌醇可以阻止或减缓T1D受试者的GFR下降，我们将有一种简单、安全和廉价的干预措施来预防或延缓T1D患者的肾衰竭，这种干预可以在临床上可以检测到的最早阶段应用。从公共卫生和糖尿病患者的角度来看，这一发现的重要性怎么说都不为过。 公共卫生相关性：我们提议的试验如果成功，将引入一种新的药物干预措施来预防或延迟T1D的肾衰竭。由此导致的发病率和死亡率的降低将对T1D患者的生活以及整个社会产生重大影响，显著降低与这种情况相关的人力和经济成本。

DESCRIPTION (provided by applicant): 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 the Joslin Diabetes Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, and the Steno Diabetes Center in Denmark. With the support of NIH grant R03 DK094484, we have designed an international four-year, multi-center, double-blind, placebo- controlled, randomized clinical trial to evaluate the efficacy of the urate-lowering drug allopurinol, as compared to placebo, in reducing kidney function loss among subjects with T1D. The trial will include a total of 400 T1D patients at high risk for GFR loss because of increased albuminuria and a relatively high serum uric acid (e 4.5 mg/dl), who still have only mildly or moderately decreased renal function (GFR=45-99 ml/min/1.73 m2). The primary endpoint of the study will be the GFR (as measured by the iohexol plasma disappearance) at the end of the 4-year intervention. We have been recently funded by the Juvenile Diabetes Research Foundation to conduct a small pilot study in two centers (Joslin and Steno) with 30 subjects/group, which will establish the feasibilit of such a trial and pilot all of its clinical research procedures and data flow and management. With the R34 support, we intend to use this and other sources of information to bring this clinical trial closer to implementation by accomplishing the following Specific Aims: 1. To compile the Manual of Operations. 2. To obtain IRB approval at all study sites. 3. To develop recruitment strategies at each center, including the establishment of relationships with satellite centers. 4. To establish drug distribution centers for this international trial. 5. To develop the tools and infrastructure for data management, quality control, and research oversight. 6. To develop a data and safety monitoring plan. By accomplishing these aims, we will be ready to start recruiting patients for the pivotal trial as soon as this is funded. If we can demonstrate that allopurinol can halt or slow GFR decline in T1D subjects, we will have a simple, 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 significantthis finding would be, both from the perspective of public health and that of persons with diabetes. PUBLIC HEALTH RELEVANCE: The trial that we propose, if successful, will introduce a new pharmacological intervention to prevent or delay kidney failure in T1D. The reduction in morbidity and mortality resulting from this would have a major impact on the lives of T1D patients as well as on society at large, significantly reducing the human and financial costs associated with this condition.