Feasibility study of empagliflozin in patients with autosomal dominant polycystic kidney disease

恩格列净治疗常染色体显性多囊肾病的可行性研究

基本信息

批准号：
10684097
负责人：
Michel Benjamin Chonchol
金额：
$ 28.82万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684097
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adherence Adverse event Affect Animal Model Anti-Inflammatory Agents Antioxidants Aorta Arteries Autosomal Dominant Polycystic Kidney Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Chronic Kidney Failure Clinical Clinical Trials Cyst Cystic Kidney Diseases Cystic kidney Data Development Diabetes Mellitus Disease Disease Progression Disease model Diuresis Dose Elasticity End stage renal failure Epithelial Cell Proliferation Epithelial cyst Etiology Event Exclusion Feasibility Studies Fibrosis Frequencies Functional disorder Genetic Diseases Genitourinary System Infection Glomerular Filtration Rate Glucose Goals Growth Growth and Development function Health Hereditary Disease Individual Injury Intervention Intervention Studies Investigation Kidney Kidney Diseases Life Liquid substance Macula densa Magnetic Resonance Imaging Measurement Measures Modeling Morbidity - disease rate Natriuresis Osmosis Outcome Oxygen Participant Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Physiologic pulse Placebos Plasma Quality of life Randomized Rattus Renal function Research Rodent Safety Sample Size Sodium Specific qualifier value Symptoms Testing Tubular formation Urinary tract Vasopressin Receptor Vasopressins antagonist arterial stiffness constriction cost diabetic disorder risk double-blind placebo controlled trial efficacy clinical trial experience health related quality of life high risk improved inhibitor insight interest loss of function mortality non-diabetic pressure progression risk randomized trial randomized, clinical trials rat KIM-1 protein receptor expression safety assessment safety testing side effect standard of care success symporter tolvaptan urinary

项目摘要

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end- stage kidney disease. Despite decades of research, tolvaptan is the only approved intervention in ADPKD. However, tolvaptan does not target cardiovascular complications of ADPKD and is constrained by high cost and side effects that limit adherence. Therefore, there is an urgent need for a well-tolerated alternative intervention to slow ADPKD progression and improve vascular health. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) have a track record of tolerability and safety in patients with proteinuric diabetic and non- diabetic kidney disease. Trials of SGLT2i in these conditions have been extremely encouraging, and these treatments are highly likely to become the standard of care for diabetic and non-diabetic kidney disease; however, the mechanisms of action are not fully elucidated, and may be non-specific to disease etiology. The potential benefit of SGLT2i has not been examined in patients with ADPKD, as major trials have excluded such patients. There are also potential benefits of SGLT2i to ADPKD patients beyond slowing loss of kidney function, as this class of drugs provide a cardiovascular mortality benefit for patients across the CKD spectrum. Studies testing the effects of SGLT2i in animal models of PKD have yield conflicting results. Five weeks of treatment with an SGLT1 and SLGT2 inhibitor phlorizon was shown to inhibit cystogenesis in the Han:SPRD rat model of PKD. The mechanisms by which SGLT2i slows cystic renal disease progression may be related to inhibition of cyst epithelial cell proliferation. SGLT2i have also antioxidant and anti-inflammatory actions, which are important for reducing fibrosis and improving vascular health, both of which occur in early stages of ADPKD. While many changes likely contribute to the development of arterial dysfunction in patients with ADPKD, among those of greatest concern is the development of stiffening of large elastic arteries, typically assessed by aortic pulse wave velocity (aPWV). We propose a pilot randomized clinical trial to determine the safety and tolerability of empagliflozin in ADPKD patients. To achieve this, we will conduct a 12-month parallel- group, randomized, double-blind, placebo-controlled trial in 50 ADPKD patients with an eGFR 30-90 mL/min/1.73m2. Secondary, exploratory endpoints will determine the effect of empagliflozin on kidney volume, kidney function, aPWV, plasma copeptin levels, urinary kidney injury molecule-1 (KIM-1) and quality of life. Specific Aim 1: To determine the feasibility, in terms of safety and tolerability, of prescribing empagliflozin 25 mg once a day in ADPKD patients at risk for progression with an eGFR of 30-90 mL/min/1.73m2. Specific Aim 2: To derive preliminary estimates of the effect of empagliflozin compared to placebo on 12- month change in a) total kidney volume by magnetic resonance imaging, b) eGFR, c) plasma copeptin levels (a marker of vasopressin secretion), d) urinary KIM-1 (a marker of tubular injury), e) aPWV; and f) ADPKD- specific health-related quality of life (HRQoL) as quantified by the ADPKD-Impact Scale.

项目概要常染色体显性多囊肾病 (ADPKD) 是一种常见的遗传性疾病，可导致最终阶段肾脏疾病。尽管经过数十年的研究，托伐普坦是唯一被批准的 ADPKD 干预措施。然而，托伐普坦并不针对 ADPKD 的心血管并发症，并且受到高成本的限制以及限制依从性的副作用。因此，迫切需要一种耐受性良好的替代品干预以减缓 ADPKD 进展并改善血管健康。钠-葡萄糖协同转运蛋白-2 抑制剂（SGLT2i）在蛋白尿糖尿病和非糖尿病患者中具有耐受性和安全性的记录。糖尿病肾病。在这些条件下进行的 SGLT2i 试验非常令人鼓舞，并且这些治疗很可能成为糖尿病和非糖尿病肾病的标准治疗；然而，其作用机制尚未完全阐明，并且可能不特定于疾病病因学。这 SGLT2i 的潜在益处尚未在 ADPKD 患者中进行检验，因为主要试验已排除此类情况患者。除了减缓肾脏丧失之外，SGLT2i 对 ADPKD 患者还有潜在的好处功能，因为此类药物为整个 CKD 谱系的患者提供了心血管死亡率方面的益处。测试 SGLT2i 在 PKD 动物模型中的作用的研究得出了相互矛盾的结果。五周的使用 SGLT1 和 SLGT2 抑制剂 phlorizon 治疗可抑制 Han:SPRD 中的囊肿发生 PKD 大鼠模型。 SGLT2i 减缓囊性肾病进展的机制可能与抑制囊肿上皮细胞增殖。 SGLT2i 还具有抗氧化和抗炎作用，对于减少纤维化和改善血管健康很重要，这两者都发生在早期阶段 ADPKD。虽然许多变化可能导致患者动脉功能障碍的发生 ADPKD，其中最令人担忧的是大弹性动脉硬化的发展，通常是通过主动脉脉搏波速度（aPWV）进行评估。我们建议进行一项试点随机临床试验来确定 ADPKD 患者恩格列净的安全性和耐受性。为了实现这一目标，我们将进行为期 12 个月的平行在 50 名 eGFR 30-90 的 ADPKD 患者中进行的随机、双盲、安慰剂对照试验毫升/分钟/1.73 平方米。次要的探索性终点将确定恩格列净对肾脏体积的影响，肾功能、aPWV、血浆和肽素水平、尿肾损伤分子-1 (KIM-1) 和生活质量。具体目标 1：确定恩格列净 25 处方的安全性和耐受性的可行性对于 eGFR 为 30-90 mL/min/1.73m2 且有进展风险的 ADPKD 患者，每天一次 1 毫克。具体目标 2：初步估计恩格列净与安慰剂相比对 12- a) 磁共振成像显示的肾脏总体积、b) eGFR、c) 血浆和肽素水平的每月变化（加压素分泌的标志物），d) 尿 KIM-1（肾小管损伤的标志物），e) aPWV； f) ADPKD- 通过 ADPKD 影响量表量化的特定健康相关生活质量 (HRQoL)。