Design of 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设计

• 批准号: 8250159
• 负责人: Alessandro Doria
• 金额: $ 10.67万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250159
• 关键词: Agreement; Algorithms; Allopurinol; Biochemical; Blood Pressure; Chronic Kidney Failure; Clinical Trials; Cohort Studies; Colorado; Complement; Complications of Diabetes Mellitus; Contracts; Databases; Denmark; Diabetes Mellitus; Diabetic Nephropathy; Dose; Double-Blind Method; End stage renal failure; Evidence based intervention; Financial cost; Glomerular Filtration Rate; Goals; Gout; Grant; Human; Incidence; Individual; Injury; Institutional Review Boards; Insulin-Dependent Diabetes Mellitus; Intervention; Iohexol; Kidney; Kidney Diseases; Kidney Failure; Left; Manuals; Measurement; Measures; Michigan; Microalbuminuria; Minnesota; Morbidity - disease rate; Natural History; Patients; Persons; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Population Sizes; Positioning Attribute; Prospective Studies; Protocols documentation; Public Health; Randomized Clinical Trials; Renal function; Renin-Angiotensin System; Research Infrastructure; Research Personnel; Residual state; Risk; Sample Size; Schedule; Series; Serum; Site; Societies; Solid; Specific qualifier value; Staging; Steno; Study Subject; Testing; Translating; Universities; Urate; Uric Acid; Visit; Work; arm; base; blood pressure regulation; clinical research site; design; diabetic patient; follow-up; high risk; macroalbuminuria; meetings; mortality; non-diabetic; novel; operation; patient population; prevent; symposium

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 (RASB), 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 a consortium that includes investigators from the Joslin Diabetes Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, and the Steno Diabetes Center. Currently, we are envisioning a four-year, multi-center, double- blind, placebo-controlled, randomized clinical trial evaluating the efficacy of the urate-lowering drug allopurinol, as compared to placebo, in reducing kidney function loss among subjects with T1D. The trial will specifically target T1D patients with microalbuminuria or moderate macroalbuminuria and serum uric acid levels e 5 mg/dl, since these are the patients who are at very high risk of having rapid rates of GFR decline and might most benefit from reductions in uric acid levels. Study subjects will be required to have a GFR e 60 ml/min, consistent with the goal of intervening relatively early in the natural history of kidney disease, when kidney function can still be preserved, rather than at later stages when structural changes are far advanced and most of kidney function is already lost. 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. Preliminary calculations suggest that ~200 subjects in each treatment arm would provide us with reasonable power to detect a clinically meaningful and achievable reduction in GFR decline in the allopurinol as compared to the placebo group. With the R03 support, we intend to bring this study concept closer to implementation by accomplishing the following Specific Aims: 1.To finalize the Study Protocol; 2.To identify the best site specific mechanisms to query the respective patient databases for the quickest identification of eligible subjects; 3.To prepare a Manual of Operation; 4.To file IRB applications at all study sites. By accomplishing these aims, we will be optimally positioned to successfully apply for an R34 grant, during which we will establish the clinical trial infrastructue and test it in a vanguard phase of the trial. If we can then demonstrate in the full trial 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 discovery would be, both from the perspective of public health and that of individual diabetic patients. 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，并且引入了肾素-血管紧张素系统阻滞剂（RASB）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降低T1D患者肾小球滤过率（GFR）损失，我们建立了一个联盟，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、密歇根大学和Steno糖尿病中心的研究人员。目前，我们正在设想一项为期四年、多中心、双盲、安慰剂对照、随机临床试验，评估降尿酸药物别嘌呤醇与安慰剂相比在减少T1D患者肾功能丧失方面的疗效。该试验将专门针对患有微量白蛋白尿或中度大量白蛋白尿且血清尿酸水平为5 mg/dl的T1D患者，因为这些患者GFR快速下降的风险非常高，并且可能从降低尿酸水平中获益最多。研究对象将被要求GFR为60 ml/min，这与在肾脏疾病自然史中相对早期干预的目标是一致的，此时肾脏功能仍然可以保留