A pilot study of fenofibrate to prevent kidney function loss in type 1 diabetes

非诺贝特预防 1 型糖尿病肾功能丧失的初步研究

• 批准号: 10675516
• 负责人: Alessandro Doria
• 金额: $ 34.16万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675516
• 关键词: Accounting; Acute; Aging; Agonist; Allopurinol; Biological Markers; Canada; Characteristics; Clinical; Clinical Trials; Creatinine; Data; Denmark; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dyslipidemias; Effectiveness; End stage renal failure; Enrollment; Evidence based intervention; Fenofibrate; Financial cost; Generic Drugs; Human; Incidence; Individual; Infrastructure; Insulin-Dependent Diabetes Mellitus; Intervention; Iohexol; Kidney; Long-Term Effects; Masks; Measures; Methodology; Mission; Morbidity - disease rate; Morphologic artifacts; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PPAR alpha; Participant; Patients; Persons; Pharmaceutical Preparations; Physiological; Pilot Projects; Placebos; Plasma; Population; Production; Randomized; Renal function; Renin-Angiotensin System; Research; Research Personnel; Residual state; Risk; Safety; Serum; Site; Societies; Time; Translating; Tubular formation; Uric Acid; biomarker identification; blood pressure control; design; disorder risk; effectiveness evaluation; evidence based guidelines; experience; high risk; improved; inhibitor; loss of function; medication safety; mortality; novel; prevent; renal damage; response; trend; trial design

SUMMARY Despite improvements in the past 20 years in glycemic and blood pressure control, and the introduction of “reno-protective” drugs such as renin-angiotensin system blockers (RASB), the overall incidence of end- stage kidney disease (ESKD) in type 1 diabetes (T1D) remains high. To seek new treatments to prevent diabetic kidney disease (DKD) and/or slow its progression to ESKD in T1D, we have established a unique consortium of high-quality academic centers, which we have named PERL (Preventing Early Renal Function Loss in Diabetes) to emphasize the focus on intervening relatively early in the course of DKD in T1D, when renal damage can more likely be slowed or stopped. Findings from the FIELD and ACCORD trials suggest a reno-protective effect of the PPAR-alpha agonist fenofibrate, raising the exciting possibility of using this inexpensive generic drug to prevent GFR decline in persons with T1D. These data, however, were obtained through post-hoc analyses of T2D populations with clinical characteristics optimized for CVD studies. Thus, a clinical trial specifically designed to evaluate effects on GFR decline is required to firmly establish a DKD indication for fenofibrate in T1D. As a first step, and in response to FOA PAS-20-160 “Small R01s for clinical trials targeting diseases within the mission of NIDDK”, we have designed a pilot study including 40 participants with T1D and early-to-moderate DKD, at high risk of ESKD, who will be enrolled at two of the PERL sites and randomized in a 1:1 ratio to treatment with fenofibrate or placebo for 18 months. Through this pilot study we will: 1. Define the nature of the acute effect of fenofibrate on kidney function. It remains unclear whether the eGFR reduction observed at the beginning of fenofibrate treatment is an artifact of fenofibrate-induced changes in creatinine production and/or renal tubular handling, or corresponds to an actual reduction in GFR. We will resolve this controversy, which has crucial implications for the pivotal trial design, by directly measuring GFR by plasma iohexol disappearance – a methodology in which PERL sites are experienced. 2. Generate further data on the long-term effects of fenofibrate on GFR decline in persons with T1D and DKD who are at high risk of rapid GFR decline and ESKD. The positive effects of fenofibrate in FIELD and ACCORD were observed in individuals who were not selected for having DKD and who, if untreated, had a mean GFR decline barely above the physiological decline due to aging. To make a compelling case for a pivotal trial for kidney outcomes, it is crucial to generate preliminary data on the effectiveness and safety of this drug in persons selected for having DKD and being rapidly progressing towards ESKD. 3. Determine the effects of fenofibrate on biomarkers of increased risk of fast GFR decline. A salutary effect of fenofibrate on one or more of these biomarkers will corroborate any trend of a fenofibrate benefit identified in Aim 2. With the results of this pilot, we will be optimally prepared to apply to NIDDK for support of a pivotal trial to establish a kidney indication for fenofibrate in T1D.

概括 尽管过去20年来在血压和血压控制方面有所改善，并引入了 “肾脏保护”药物，例如肾素 - 血管紧张素系统阻滞剂（RASB），末端的总体事件 1型糖尿病（T1D）中的肾脏疾病（ESKD）仍然很高。寻求新的治疗以防止 糖尿病肾脏疾病（DKD）和/或减慢其在T1D中的ESKD的进展，我们建立了一个独特的 高质量学术中心的财团，我们将其命名为Perl（预防早期肾功能） 糖尿病的损失）强调在T1D的DKD过程中相对较早的介入的重点 肾脏损害更有可能放慢或停止。现场的发现和协议试验表明 PPAR-Alpha激动剂Fenodribrate的肾化保护作用，提高了使用此功能的激动人心的可能性 廉价的通用药物可防止T1D患者的GFR下降。但是，这些数据得到了 通过对具有针对CVD研究优化的临床特征的T2D种群的事后分析。那， 一项专门用于评估对GFR下降影响的临床试验需要牢固建立DKD 在T1D中表明非诺贝特的指示。作为第一步，并回应FOA PAS-20-160“临床的小R01 针对Niddk任务中疾病的试验”，我们设计了一项试点研究，其中包括40个 具有T1D和早期DKD的参与者，ESKD的高风险很高，他们将被注册 perl位点，并以1：1的比率随机分别与非诺贝特或安慰剂治疗18个月。通过 这项试验研究我们将：1。定义非诺贝特对肾功能的急性效应的性质。 尚不清楚在非诺贝特治疗开始时观察到的EGFR减少是否是 非诺贝特诱导的肌酐产生和/或肾小管处理的变化的伪像的伪像 实际减少GFR。我们将解决这一争议，这对关键有关键的影响 试验设计，通过血浆iohexol消失直接测量GFR - 一种方法，其中Perl 站点是经验丰富的。 2。生成有关非诺贝特对GFR下降的长期影响的进一步数据 在患有GFR快速下降和ESKD的高风险的T1D和DKD的人中。积极 在未被选中被选中的个体中观察到非诺贝特的影响 DKD和如果不加以治疗的人的平均GFR下降几乎高于衰老引起的身体下降。 为了为肾脏结局进行关键试验的令人信服的案例，生成初步数据至关重要 关于该药物在被选为DKD并迅速迅速的人中的有效性和安全性 走向ESKD。 3。确定非诺贝特对增加风险的生物标志物的影响 快速GFR下降。非诺贝特对其中一种或多种生物标志物的有益效果将证实任何 在AIM 2中确定的非诺贝特益处的趋势。随着该飞行员的结果，我们将为我们提供最佳准备 向NIDDK申请支持一个关键试验，以建立T1D中非诺贝特的肾脏指示。