Design of 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“肾脏保护”药物，如肾素-血管紧张素系统阻滞剂（RASB），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，我们建立了一个包括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Steno糖尿病中心研究人员的联盟。目前，我们正在设想一项为期4年、多中心、双盲、安慰剂对照、随机临床试验，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。该试验将专门针对微量白蛋白尿或中度大量白蛋白尿且血清尿酸水平<5 mg/dl的T1 D患者，因为这些患者具有GFR快速下降的极高风险，并且可能从尿酸水平降低中获益最多。要求研究受试者的GFR e 60 ml/min，这与在肾脏疾病自然史的相对早期进行干预的目标一致，此时肾功能仍可保留，而不是 而不是在后期，当结构变化非常严重时，大部分肾功能已经丧失。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）。初步计算表明，与安慰剂组相比，每个治疗组约200例受试者将为我们提供合理的把握度，以检测别嘌呤醇组GFR下降的临床意义和可实现的降低。在R 03的支持下，我们打算通过实现以下具体目标使本研究概念更接近于实施：1.最终确定研究方案; 2.确定最佳研究中心特定机制，以查询相应患者数据库，从而最快地识别合格受试者; 3.编写操作手册; 4.在所有研究中心提交IRB申请。通过实现这些目标，我们将处于成功申请R34补助金的最佳位置，在此期间，我们将建立临床试验基础设施，并在试验的先锋阶段进行测试。如果我们能够在完整的试验中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，廉价的干预措施来预防或延迟T1 D肾衰竭，可以在临床上最早可检测到的肾损伤阶段应用。无论从公共卫生还是从糖尿病患者个人的角度来看，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。

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.