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

描述（由申请人提供）：尽管在过去20年中血糖和血压控制有所改善，并且引入了“肾素-血管紧张素系统阻滞剂”等“肾保护”药物，但1型糖尿病（T1D）的终末期肾病（ESRD）发生率并未下降。迫切需要新的治疗方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，中度升高的血清尿酸是T1D患者慢性肾脏疾病风险增加和肾功能丧失率增加的一个强有力的独立预测因子。为了研究降低尿酸是否可以减少T1D患者肾小球滤过率（GFR）损失，我们建立了PERL（预防糖尿病早期肾功能丧失）联盟，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拨款R03 DK094484的支持下，我们设计了一项为期四年，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，降尿酸药物别嘌呤醇在减少T1D患者肾功能丧失方面的疗效。该试验将包括总共400名T1D患者，由于蛋白尿增加和相对较高的血清尿酸（4.5 mg/dl），他们有GFR损失的高风险，但仍然只有轻度或中度肾功能下降（GFR=45-99 ml/min/1.73 m2）。该研究的主要终点将是4年干预结束时的GFR（通过碘己醇血浆消失来测量）。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）进行了一个小规模的试点研究，有30名受试者/组，这将建立这样一个试验的可行性，并试点其所有临床研究程序、数据流和管理。在R34的支持下，我们打算利用这一信息和其他信息来源将其推向临床

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.