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

总结 尽管在过去20年中血糖和血压控制有所改善， “肾脏保护”药物，如肾素-血管紧张素系统阻滞剂（RASB），终末- 1型糖尿病（T1 D）中的阶段性肾病（ESKD）仍然很高。寻求新的治疗方法来预防 糖尿病肾病（DKD）和/或减缓其在T1 D中向ESKD的进展，我们已经建立了一个独特的 高质量学术中心联盟，我们将其命名为PERL（预防早期肾功能 糖尿病丢失），以强调在T1 D DKD病程中相对早期进行干预， 肾损害更可能被减缓或停止。FIELD和雅阁试验的结果表明， PPAR-alpha激动剂非诺贝特的肾脏保护作用，提高了使用这种激动剂的可能性。 廉价的仿制药，以防止GFR下降的人与T1 D。然而，这些数据是在 通过对具有针对CVD研究优化的临床特征的T2 D人群进行事后分析。因此，在本发明中， 需要专门设计用于评估对GFR下降的影响的临床试验来牢固地建立DKD T1 D患者非诺贝特适应症。作为第一步，并响应FOA PAS-20-160“临床用小型R 01” 针对NIDDK使命内疾病的试验”，我们设计了一项试点研究，包括40 患有T1 D和早期至中度DKD的受试者，ESKD的高风险，他们将入组其中两个 PERL研究中心，并以1：1的比例随机接受非诺贝特或安慰剂治疗18个月。通过 这项试点研究，我们将：1。明确非诺贝特对肾功能急性影响的性质。它 目前尚不清楚在非诺贝特治疗开始时观察到的eGFR降低是否是 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 GFR的实际下降。我们将解决这一争议，这对关键的 试验设计，通过血浆碘海醇消失直接测量GFR-PERL 网站经验丰富。2.生成关于非诺贝特对GFR下降的长期影响的进一步数据 在GFR快速下降和ESKD高风险的T1 D和DKD患者中。的积极 非诺贝特在FIELD和雅阁中的作用在未被选择为具有 DKD患者，如果不治疗，其平均GFR下降仅略高于由于衰老引起的生理下降。 为了使一项关于肾脏结局的关键试验具有令人信服的理由，生成初步数据至关重要 本品在选择的DKD患者中的有效性和安全性， 向ESKD迈进。3.确定非诺贝特对以下风险增加的生物标志物的影响： GFR快速下降。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 目标2中确定的非诺贝特获益趋势。有了这一试点的结果，我们将做好最佳准备， 向NIDDK申请支持一项关键试验，以确定非诺贝特在T1 D中的肾脏适应症。

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.