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

基本信息

批准号：
10274529
负责人：
Alessandro Doria
金额：
$ 37.55万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10274529
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 Gold 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 Protective Agents Randomized Renal function Renin-Angiotensin System Research Research Personnel Residual state Risk Safety Serum Site Societies Time Translating Tubular formation Uric Acid blood pressure regulation design disorder risk effectiveness evaluation experience high risk inhibitor/antagonist loss of function medication safety mortality novel prevent protective effect renal damage response trend trial design

项目摘要

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 年在血糖和血压控制方面取得了进步，并且引入了 “肾病保护”药物，如肾素血管紧张素系统阻滞剂（RASB），最终的总体发生率 1 型糖尿病 (T1D) 阶段肾病 (ESKD) 的发病率仍然很高，需要寻求新的治疗方法来预防。糖尿病肾病 (DKD) 和/或减缓其进展为 T1D 中的 ESKD，我们已经建立了独特的高质量学术中心联盟，我们将其命名为 PERL（预防早期肾功能）糖尿病损失）强调在 T1D 的 DKD 病程中相对早期进行干预的重点，当 Field 和 ACCORD 试验的结果表明，肾损伤更有可能被减缓或停止。 PPAR-α 激动剂非诺贝特的肾脏保护作用，提高了使用该药物的令人兴奋的可能性然而，这些数据是通过廉价仿制药来预防 T1D 患者 GFR 下降的。通过针对 CVD 研究优化临床特征的 T2D 人群的事后分析，需要专门设计用于评估对 GFR 下降的影响的临床试验才能牢固地建立 DKD 作为第一步，响应 FOA PAS-20-160“临床小 R01”。针对 NIDDK 使命范围内的疾病进行的试验”，我们设计了一项试点研究，其中包括 40 患有 T1D 和早期至中度 DKD 且 ESKD 高风险的参与者，他们将在其中两个 PERL 站点并以 1:1 的比例随机分配非诺贝特或安慰剂治疗 18 个月。在这项试点研究中，我们将： 1. 定义非诺贝特对肾功能的急性影响的性质。目前尚不清楚非诺贝特治疗开始时观察到的 eGFR 降低是否是一种非诺贝特诱导的肌酐产生和/或肾小管处理变化的伪影，或相应的我们将解决这一争议，这对关键的问题具有至关重要的影响。试验设计，通过血浆碘海醇消失直接测量 GFR——一种 PERL 方法 2. 生成有关非诺贝特对 GFR 下降的长期影响的进一步数据。对于 GFR 快速下降和 ESKD 风险较高的 T1D 和 DKD 患者。在未选择的个体中观察到非诺贝特在 FIELD 和 ACCORD 中的作用 DKD 患者如果不接受治疗，其平均 GFR 下降仅略高于因衰老而导致的生理下降。为了为肾脏结果的关键试验提供令人信服的理由，生成初步数据至关重要该药物对患有 DKD 并迅速接受治疗的患者的有效性和安全性 3. 确定非诺贝特对 ESKD 风险增加的生物标志物的影响。非诺贝特对这些生物标志物中的一种或多种的有益作用将证实任何 GFR 快速下降。目标 2 中确定的非诺贝特益处的趋势。根据该试点的结果，我们将做好最佳准备向 NIDDK 申请支持一项关键试验，以确定非诺贝特治疗 T1D 的肾脏适应症。