Liver Cirrhosis Network: Clinical Research Center - Mayo Clinic

肝硬化网络：临床研究中心 - 梅奥诊所

• 批准号: 10700154
• 负责人: VIJAY H. SHAH
• 金额: $ 21.04万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700154
• 关键词: Animal Model; Anticoagulation; Artificial Intelligence; Attenuated; Biological Specimen Banks; Blood Vessels; Cardiovascular system; Cessation of life; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials; Collection; Compensation; Conduct Clinical Trials; Data; Data Coordinating Center; Data Set; Databases; Development; Disease; Disease Progression; Electrocardiogram; Endothelium; Etiology; Event; Fibrosis; Foundations; Future; Generations; Goals; Hemorrhage; Hepatic; Hepatic Stellate Cell; Human; Image; Incidence; Inflammation; Laboratories; Length; Liver; Liver Cirrhosis; Liver diseases; Longitudinal Studies; Low-Molecular-Weight Heparin; Magnetic Resonance Elastography; Measures; Monitor; Natural History; Observational Study; Outcome; Pathogenicity; Patients; Phase; Phase III Clinical Trials; Placebos; Portal Hypertension; Portal Pressure; Prevention; Primary carcinoma of the liver cells; Prognostic Marker; Randomized; Research; Research Personnel; Resolution; Risk; Safety; Simvastatin; Telomere Shortening; Testing; Therapeutic; Thrombosis; Translational Research; Treatment Efficacy; Validation; Varicosity; circulating biomarkers; effective therapy; efficacy evaluation; efficacy study; efficacy trial; end stage liver disease; extracellular; follow-up; improved; improved outcome; intrahepatic; liver function; liver inflammation; longitudinal database; machine learning prediction algorithm; meetings; mortality; neutrophil; novel; novel marker; novel therapeutics; preclinical study; prediction algorithm; preservation; prevent; primary endpoint; prognostic; prospective; radiological imaging; randomized trial; response; restoration; safety assessment; safety study; secondary endpoint; success; supervised learning; telomere; therapeutic development; therapeutic target; thrombotic; tool; translational study; trial design

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.

项目摘要/摘要 缺乏旨在预防膀胱炎相关并发症发展的治疗方法。他汀类药物已经 显示改善肝功能和减轻门脉高压，但缺乏明确的研究。我们 研究团队在肝硬化和门脉高压方面拥有深厚的专业知识，包括临床，翻译， 疾病的实验室方面。我们在本提案中的目标是：目标1。进行一项前瞻性、多中心、 对代偿性肝硬化患者进行的观察性研究， 发现新的机制和治疗靶点。我们会整合一个纵向数据库，以（a） 提供关于肝硬化的自然史和结果的独特信息，和（B）支持翻译 研究（在目标3中提出）。该稳健的多中心数据集将用于开发和验证 人工智能衍生的算法用于预测失代偿结合广泛的临床， 实验室和放射学数据，包括磁共振弹性成像和心电图。目标2. 进行一项辛伐他汀与安慰剂比较的多中心前瞻性随机III期临床试验 改善代偿期肝硬化患者的预后。这一目标将检验以下假设： 辛伐他汀在减少肝硬化并发症和总死亡率方面上级安慰剂。该项3期 疗效试验将患者随机分为辛伐他汀20 mg组或安慰剂组，每日一次，中位随访时间为36个月。 主要终点将是按顺序分析的静脉曲张、失代偿事件或死亡的发生 结果基于六个预后阶段。次要终点将包括纤维化消退、 肝细胞癌和心血管并发症。目标3。确定新的致病靶点， 通过2个子目标治疗肝硬化进展：子目标3a。为了研究端粒的磨损率， 肝硬化进展和失代偿。在晚期肝硬化中观察到端粒缩短 并且临床前研究已经显示随着端粒长度恢复而减少的纤维化。但是，率 肝硬化中端粒磨损及其与疾病进展的关系仍不清楚。我们的建议将 作为未来研究的基础，评估旨在保留端粒长度的新疗法， 肝硬化和他汀类药物的影响。次级目标3b.测量中性粒细胞外循环标志物 陷阱（NET）及其与肝失代偿发展的相关性。抗凝剂已经 在一个小规模的肝硬化患者试验中显示，我们集团最近 显示NET驱动肝内血栓形成，抑制NET可降低临床前门静脉压力， 问题研究因此，这一子目标的结果将作为未来人类研究的基础。 旨在破坏肝脏中NET的新疗法。我们的中心和团队拥有丰富的临床专业知识， 因此，我们已经做好准备进行这些研究。