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

别嘌呤醇预防 1 型糖尿病 GFR 损失的多中心临床试验

• 批准号: 8445008
• 负责人: Alessandro Doria
• 金额: $ 18.97万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445008
• 关键词: Agreement; Albuminuria; Allopurinol; Chronic Kidney Failure; Clinical Research; Clinical Trials; Cohort Studies; Colorado; Community Health Centers; Complement; Complications of Diabetes Mellitus; Contracts; Data; Denmark; Diabetes Mellitus; Diabetic Nephropathy; Double-Blind Method; End stage renal failure; Evidence based intervention; Financial cost; Foundations; Funding; Glomerular Filtration Rate; Goals; Gout; Grant; Human; Incidence; Injury; Institutional Review Boards; Insulin-Dependent Diabetes Mellitus; International; Intervention; Iohexol; Kidney; Kidney Failure; Left; Manuals; Measures; Michigan; Microalbuminuria; Minnesota; Monitor; Morbidity - disease rate; Names; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Plasma; Procedures; Prospective Studies; Protocols documentation; Public Health; Quality Control; Randomized Clinical Trials; Recruitment Activity; Renal function; Renin-Angiotensin System; Research; Research Infrastructure; Research Personnel; Residual state; Risk; Safety; Sample Size; Serum; Site; Societies; Source; Staging; Steno; Study Subject; Testing; United States National Institutes of Health; Universities; Urate; Uric Acid; arm; blood pressure regulation; data management; design; dosage; drug distribution; glycemic control; high risk; international center; macroalbuminuria; mortality; novel; operation; pilot trial; prevent; tool

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.

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“肾脏保护”药物，如肾素-血管紧张素系统阻滞剂，但1型糖尿病（T1 D）终末期肾病（ESRD）的发病率并未下降。迫切需要补充这些干预措施的新疗法。来自前瞻性研究的越来越多的证据表明，血清尿酸中度升高是T1 D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素。为了研究降低尿酸是否可以减少T1 D患者的肾小球滤过率（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基金R 03 DK 094484的支持下，我们设计了一项为期4年的国际多中心、双盲、安慰剂对照、随机临床试验，以评价降尿酸药物别嘌呤醇与安慰剂相比在减少T1 D受试者肾功能丧失方面的疗效。该试验将纳入总计400例因白蛋白尿增加和相对较高的血清尿酸（e 4.5 mg/dl）而具有GFR丧失高风险的T1 D患者，这些患者仍仅有轻度或中度肾功能下降（GFR=45-99 ml/min/1.73 m2）。本研究的主要终点将是4年干预结束时的GFR（通过碘海醇血浆消失测量）。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）进行了一项小型试点研究，每组30名受试者，这将建立这样一项试验的可行性，并试点其所有临床研究程序和数据流和管理。在R34的支持下，我们打算利用这一信息来源和其他信息来源， 通过实现以下具体目标，使试验更接近实施：1.编写操作手册。2.在所有研究中心获得IRB批准。3.制定每个中心的招聘策略，包括建立与卫星中心的关系。4.为这项国际试验建立药物配送中心。5.开发用于数据管理、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，我们将准备在获得资金后立即开始招募患者进行关键试验。如果我们能够证明别嘌呤醇可以阻止或减缓T1 D受试者的GFR下降，我们将有一个简单，安全，廉价的干预措施，以预防或延迟T1 D肾衰竭，可以应用在临床上最早可检测到的肾损伤阶段。无论从公共卫生还是糖尿病患者的角度来看，都很难夸大这一发现的重要性。 公共卫生相关性：我们提出的试验，如果成功，将引入一种新的药物干预，以预防或延迟T1 D肾衰竭。由此导致的发病率和死亡率的降低将对T1 D患者的生活以及整个社会产生重大影响，显著降低与这种病症相关的人力和财力成本。