Leveraging Clinical Trials of Diabetic Kidney Disease to Advance Biomarkers

 描述（由申请人提供）：慢性肾脏疾病（CKD）和终末期肾脏疾病（ESRD）在美国和全球范围内是一个巨大的负担。糖尿病肾病（DKD）是CKD和ESRD的最大单一病因。DKD是进行性的，很少有治疗能够改变其病程。目前，DKD的临床风险评估取决于估计的GFR（eGFR）和肾小球损伤（白蛋白尿）的测量，然而，这两种标志物不能为进展为晚期DKD提供足够的风险分层， ESRD和心血管（CV）事件。高风险进展患者的预后生物标志物的开发将有助于未来的临床试验， 事件发生率较高的患者，从而允许减少样本量，以检测具有给定相对风险降低的干预措施。此外，迫切需要确定最有可能从各种形式的强化治疗中获益的患者亚组 （预测性生物标志物），并确定更好的替代终点。通过利用来自2型糖尿病患者的三项大型临床试验（VA- NEPHRON-D、雅阁和Sun-MACRO）的数据和储存的血液和尿液样本，我们将测量来自不同途径的15种血液和尿液生物标志物，包括炎症、肾小球、肾小管损伤和肾小管间质纤维化标志物。根据这些数据，我们将推导并验证目标1中肾脏终点（GFR进展和透析）预后的生物标志物组，以及目标2中心血管事件和死亡的生物标志物组。此外，由于样本来自随机对照试验，我们将测试生物标志物的效应改变（目的3），以确定是否存在 是在试验中采用的各种干预措施（特别是双重肾素血管紧张素醛固酮阻断，强化血糖控制或降低收缩压目标）中表现出获益的亚组。这些试验的数据和样本将提供给CKD-BIOCon，用于与其他小组进行合作研究。我们还将与关键路径研究所和FDA的专家合作，通过新开发的FDA和EMA认证流程推进有前景的生物标志物，以便它们可以整合到新药开发试验的监管审查过程中。

 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) and end stage renal diseases (ESRD) represent an enormous burden in the United States and worldwide. Diabetic kidney disease (DKD) is the single largest cause of CKD and ESRD. DKD is progressive and few therapies are able to alter its course. Currently, clinical risk assessment of DKD depends upon measures of estimated GFR (eGFR) and glomerular injury (albuminuria), however, these two markers fall short of providing sufficient risk stratification for progression to advanced DKD, ESRD and cardiovascular (CV) events. Development of prognostic biomarkers of those at high risk of progression will aide both future clinical trials, by serving to enrich the enrollment with patients with a higher event rate, thereby allowing for a reduced sample size to detect an intervention with a given relative risk reduction. Moreover, there is an urgent need to identify th subgroups of patients that are most likely to drive benefit from various forms of intensive therapy (predictive biomarkers) and to identify better surrogate endpoints. By leveraging the data and stored blood and urine samples from three large clinical trials in patients with type 2 diabetes (VA- NEPHRON-D, ACCORD, and Sun-MACRO), we will measure 15 blood and urine biomarkers from diverse pathways including inflammatory, glomerular, tubule injury, and tubulointerstitial fibrosis markers. From these data, we will derive and validate biomarker panels for prognosis of renal endpoints (GFR progression and dialysis) in Aim 1 and cardiovascular events and death in Aim 2. Moreover, since the samples are derived from randomized controlled trials, we will test for effect modification by biomarkers (Aim 3) to determine if there were sub-groups that demonstrated benefit with various interventions employed in the trials (specifically, dual renin angiotensin aldosterone blockade, intensive glycemic control, or lower systolic blood pressure targets). The data and samples from these trials will be available to the CKD-BIOCon for collaborative studies with other groups. We will also collaborate with experts from the Critical Path Institute and the FDA to advance promising biomarkers through the newly developed FDA and EMA qualification processes so that they can be integrated in the regulatory review process for newer drug development trials.