Design of a Multicenter Clinical Trial of Allopurinol to Prevent GFR Loss in T1D

描述(申请人提供)：尽管在过去20年中血糖和血压控制有所改善，肾素-血管紧张素系统阻滞剂(RASB)等肾脏保护药物的引入，但1型糖尿病(T1D)的终末期肾脏疾病(ESRD)的发生率并未下降。迫切需要新的疗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，中度升高的血尿酸是T1D患者慢性肾脏疾病风险增加和肾功能损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T1D时肾小球滤过率(GFR)的损失，我们成立了一个联盟，成员包括来自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的多中心、双盲、安慰剂对照的随机临床试验，评估与安慰剂相比，降尿酸药物别嘌醇在减少T1D受试者肾功能损失方面的疗效。这项试验将专门针对有微量蛋白尿或中度大量蛋白尿和血清尿酸水平e 5 mg/dl的T1D患者，因为这些患者有非常高的GFR下降速度的风险，可能从尿酸水平的降低中受益最大。研究对象将被要求有60毫升/分钟的肾小球滤过率，这与在肾脏疾病的自然病程中相对较早地进行干预的目标是一致的，那时肾功能仍然可以被保存，而不是 而不是在结构变化非常严重、大部分肾功能已经丧失的后期阶段。研究的主要终点将是4年干预结束时的肾小球滤过率(通过碘海醇血浆消失来衡量)。初步计算表明，与安慰剂组相比，每个治疗组中约200名受试者将为我们提供合理的力量来检测别嘌醇组GFR下降的临床意义和可实现的减少。在R03的支持下，我们打算通过实现以下具体目标使这项研究的概念更接近实施：1.最终确定研究方案；2.确定最佳地点特定机制，以查询各自的患者数据库，以最快地确定符合条件的受试者；3.编写操作手册；4.在所有研究地点提交IRB申请。通过实现这些目标，我们将处于成功申请R34拨款的最佳地位，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醇可以阻止或减缓T1D受试者的GFR下降，我们将有一种简单、安全和廉价的干预措施来预防或延缓T1D患者的肾衰竭，这种干预可以在临床上可以检测到的最早阶段应用。无论是从公共健康的角度还是从糖尿病患者个人的角度来看，这一发现的意义都不能夸大。 公共卫生相关性：我们提议的试验如果成功，将引入一种新的药物干预措施来预防或延迟T1D的肾衰竭。由此导致的发病率和死亡率的降低将对T1D患者的生活以及整个社会产生重大影响，显著降低与这种情况相关的人力和经济成本。

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.