Liver Cirrhosis Network: Clinical Research Center - Mayo Clinic

项目摘要/摘要 目前还缺乏旨在预防肝硬变相关并发症发展的治疗方法。他汀类药物已经 显示可以改善肝功能和减轻门脉高压，尽管缺乏明确的研究。我们的 调查团队在肝硬变和门静脉高压症方面拥有深厚的专业知识，包括临床、翻译和 疾病的实验室方面。我们在这项建议中的目标是：目标1。进行预期的、多中心的、 代偿性肝硬变患者的观察性研究将作为基础 发现新的机制和治疗靶点。我们将合并一个纵向数据库，以(A) 提供有关肝硬变自然病史和预后的独特信息，并(B)支持翻译 研究(在目标3中提出)。这一强大的多中心数据集将用于开发和验证 基于人工智能的失代偿预测算法，结合了广泛的临床应用， 实验室和放射数据，包括磁共振弹性成像和心电图。目标2. 进行辛伐他汀与安慰剂的多中心前瞻性随机3期临床试验 改善代偿性肝硬变患者的预后。这一目标将检验这一假设 辛伐他汀在减少肝硬变并发症和总死亡率方面优于安慰剂。本阶段3 疗效试验将随机选择患者每天服用辛伐他汀20毫克或安慰剂，平均随访时间为36个月。 主要终点是发生静脉曲张、失代偿事件或按顺序分析的死亡 基于结果的六个预后阶段。次要终点将包括纤维化回归、发病率 肝细胞癌和心血管并发症。目的3.确定新的致病靶点 肝硬变进展通过2个子目标：子目标3a。为了研究人类端粒的磨损率， 肝硬变进展和失代偿。在晚期肝硬变中观察到端粒缩短 临床前研究表明，端粒长度恢复可减少纤维化。然而，这一比率 肝硬变中的端粒磨损及其与疾病进展的关系尚不清楚。我们的建议将 为未来评估旨在保持端粒长度的新疗法奠定了基础 肝硬变和他汀类药物的作用。分目标3b。中性粒细胞胞外循环标志物的检测 陷阱(Net)及其与肝脏失代偿发展的关系。抗凝血已经被 在一项对肝硬变患者的小型试验中，显示了减少肝脏失代偿的作用。我们小组最近 研究表明，在临床前，Net可促进肝内血栓形成，抑制Net可降低门脉压力 学习。因此，这一分目标的结果将作为未来人类研究调查的基础 旨在破坏肝脏中的Net的新疗法。我们的中心和团队在临床方面拥有丰富的专业知识 我们正在进行晚期肝病的试验和治疗，因此已经做好了进行这些研究的准备。

PROJECT SUMMARY/ABSTRACT Therapies aimed at preventing development of cirrhosis-related complications are lacking. Statins have been shown to improve liver function and attenuate portal hypertension although definitive studies are lacking. Our investigative team has deep expertise in cirrhosis and portal hypertension including clinical, translational, and laboratory aspects of disease. Our aims in this proposal are: Aim 1. To conduct a prospective, multicenter, observational study of patients with compensated cirrhosis that will serve as the foundation for discovery of novel mechanistic and therapeutic targets. We will consolidate a longitudinal database to (a) provide unique information on the natural history and outcomes of cirrhosis and (b) support translational research (proposed in Aim 3). This robust multicenter dataset will be used for the development and validation of an artificial intelligence-derived algorithm for prediction of decompensation combining extensive clinical, laboratory and radiographic data, including magnetic resonance elastography and electrocardiogram. Aim 2. To perform a multicenter prospective randomized phase 3 clinical trial of simvastatin versus placebo to improve outcomes in patients with compensated cirrhosis. This aim will test the hypothesis that simvastatin is superior to placebo for reducing complications of cirrhosis and overall mortality. This phase 3 efficacy trial will randomize patients to Simvastatin 20 mg or placebo daily with median follow up of 36 months. The primary endpoint will be development of varices, decompensating events or death analyzed as ordinal outcomes based six prognostic stages. Secondary endpoints will include fibrosis regression, incidence of hepatocellular carcinoma, and cardiovascular complications. Aim 3. To identify novel pathogenic targets in cirrhosis progression through 2 Sub-aims: Sub-Aim 3a. To investigate the rate of telomere attrition in cirrhosis progression and decompensation. Telomere shortening has been observed in advanced cirrhosis and preclinical studies have shown reduced fibrosis with telomere length restoration. However, the rate of telomere attrition in cirrhosis and its association with disease progression remain unknown. Our proposal will serve as the basis for future studies assessing new therapies aimed at telomere length preservation in cirrhosis and effects of statins. Sub-Aim 3b. To measure circulating markers of neutrophil extracellular traps (NETs) and its correlation to development of hepatic decompensation. Anticoagulation has been shown to reduce hepatic decompensation in a small trial of patients with cirrhosis. Our group has recently shown that NETs drive intrahepatic thrombosis, and inhibition of NETs reduces portal pressure in preclinical studies. Thus, the results of this sub-aim will serve as the foundation for future human studies investigating novel therapies aimed at disrupting NETs in the liver. Our center and team have substantial expertise in clinical trials and therapeutics for advanced liver disease and are thus well poised to conduct these studies.