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: 10310667
• 负责人: VIJAY H. SHAH
• 金额: $ 36.61万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10310667
• 关键词: Animal Model; Anticoagulation; Artificial Intelligence; Attenuated; Biological Specimen Banks; Cardiovascular system; Cessation of life; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials; Collection; Conduct Clinical Trials; Data; Data Coordinating Center; Data Set; Databases; Development; Diagnostic radiologic examination; 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; base; circulating biomarkers; effective therapy; efficacy study; efficacy trial; extracellular; follow-up; improved; improved outcome; intrahepatic; liver function; liver inflammation; longitudinal database; machine learning algorithm; meetings; mortality; neutrophil; novel; novel marker; novel therapeutics; preclinical study; prediction algorithm; preservation; prevent; primary endpoint; prognostic; prospective; randomized trial; response; restoration; safety study; secondary endpoint; success; supervised learning; telomere; therapeutic development; therapeutic target; 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 缺乏旨在防止与肝硬化有关并发症发展的疗法。他汀类药物已经是 尽管缺乏明确的研究，但显示可改善肝功能并减轻门户高血压。我们的 调查团队在肝硬化和门户高血压方面具有深厚的专业知识，包括临床，翻译和 疾病的实验室方面。我们在此提案中的目标是：目标1。 对肝硬化的患者的观察性研究将成为 发现新型机械和治疗靶标。我们将纵向数据库合并到（a） 提供有关肝硬化的自然历史和结果的独特信息，（b）支持翻译 研究（在目标3中提出）。此强大的多中心数据集将用于开发和验证 人工智能衍生的算法，用于预测代偿化的临床广泛临床， 实验室和影像学数据，包括磁共振弹性图和心电图。目标2。 执行辛伐他汀与安慰剂的多中心前瞻性随机阶段3临床试验 改善肝硬化的患者的预后。这个目标将检验以下假设 辛伐他汀优于安慰剂，可以减少肝硬化并发症的并发症。这个阶段3 疗效试验将使患者每天在36个月的中位随访中随机将辛伐他汀20毫克或安慰剂。 主要终点将是静脉曲张的发展，代偿事件代偿或死亡分析为有序的 结果基于六个预后阶段。次要终点将包括纤维化回归，发生率 肝细胞癌和心血管并发症。目标3。确定新的病原靶标 肝硬化通过2个子iams的进展：sub-aim 3a。调查端粒损耗率 肝硬化的进展和代偿作用。在晚期肝硬化中已经观察到端粒缩短 临床前研究表明，随着端粒长度的恢复，纤维化降低。但是， 肝硬化中的端粒损耗及其与疾病进展的关联仍然未知。我们的建议将 作为未来研究的基础，评估了旨在保存端粒长度的新疗法 他汀类药物的肝硬化和作用。 Sub-aim 3b。测量中性粒细胞外的循环标记 陷阱（网）及其与肝脏代偿发展发展的相关性。抗凝已经存在 在一项小型肝硬化患者的小型试验中，显示出可减少肝功能补偿。我们的小组最近有 表明网络驱动肝内血栓形成和抑制网可降低临床前的门户压力 研究。因此，该子AIM的结果将成为未来人类研究的基础 旨在破坏肝脏网的新型疗法。我们的中心和团队在临床方面具有丰富的专业知识 晚期肝病的试验和治疗疗法，因此有很好的准备进行这些研究。