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; 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）：尽管过去20年来在血管血压和血压控制方面有所改善，并且引入了“肾脏保护性”药物，例如肾素 - 血管紧张素系统阻滞剂，但1型糖尿病（T1D）中终末期肾脏疾病（ESRD）的发生率没有下降。迫切需要需要新的疗法来补充这些干预措施。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慢性肾脏疾病风险增加和T1D患者肾功能丧失率增加的强烈，独立的预测指标。为了研究尿酸降低是否可以降低T1D中的肾小球滤过率（GFR）损失，我们已经建立了包括乔斯林糖尿病中心，明尼苏达州，明尼苏达州，科罗拉多州，多伦多，多伦多和密歇根州和Steno diabetes diableck的Denbrabs的Perl（预防糖尿病的早期肾功能损失）。在NIH Grant R03 DK094484的支持下，我们设计了一个四年制的，多中心，双盲，安慰剂控制的，随机的，随机的临床试验，以评估与安慰剂相比，在减少T1D受试者中的肾脏肾脏功能损失方面，与尿酸盐毒药的疗效相比。该试验将包括400名T1D患者，因为蛋白尿症增加和相对较高的血清尿酸（E 4.5 mg/dL），其GFR损失的风险很高，他们仍然只有轻度或中度降低肾功能（GFR = 45-99 mL/min/min/min/min/min/1.73 m2）。该研究的主要终点是在4年干预结束时的GFR（由iohexol血浆消失衡量）。我们最近由少年糖尿病研究基金会资助了我们在两个中心（Joslin and Steno）进行的小型试点研究，该研究将建立此类试验的可行性，并试点其所有临床研究程序以及数据流量和数据流和管理。在R34的支持下，我们打算使用此信息来源和其他信息来实现此临床 通过实现以下特定目的，可以更接近实施的审判：1。编译操作手册。 2。在所有研究地点获得IRB批准。 3。在每个中心制定招聘策略，包括与卫星中心建立关系。 4。建立该国际试验的药物分配中心。 5。开发用于数据管理，质量控制和研究监督的工具和基础架构。 6。制定数据和安全监控计划。通过实现这些目标，我们将准备好一旦资助这一点，就可以开始招募患者进行关键试验。如果我们可以证明别嘌呤醇可以停止或减慢T1D受试者的GFR下降，那么我们将进行简单，安全且廉价的干预措施，以防止或延迟T1D中的肾衰竭，以最早的临床可检测到的肾脏损伤阶段应用。从公共卫生的角度和糖尿病患者的角度来看，很难高估这一发现的重要性。 公共卫生相关性：我们提出的试验（如果成功）将引入新的药理干预措施，以预防或延迟T1D肾脏衰竭。由于此导致的发病率和死亡率的降低将对T1D患者以及整个社会的生活产生重大影响，从而大大降低了与这种情况相关的人类和财务成本。