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.

项目总结/文摘