Strategies and Therapies for Outcomes Prevention in Cirrhosis: The STOP-C Liver Cirrhosis Network

肝硬化结果预防的策略和治疗：STOP-C 肝硬化网络

• 批准号: 10700170
• 负责人: ROBERT S BROWN
• 金额: $ 62.28万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700170
• 关键词: Alcoholic Liver Diseases; Behavior; Behavioral; Biological Markers; Cessation of life; Cholestasis; Cirrhosis; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cohort Studies; Compensation; Complex; Cryptogenic cirrhosis; Data; Data Set; Development; Disease Progression; Effectiveness; Electronic Health Record; Electronics; Etiology; Fatty acid glycerol esters; Future; Generations; Health; Hepatic; Hepatotoxicity; Human; Incidence; Individual; Inflammation; Intervention; Intervention Trial; Knowledge; Life; Lipids; Lipoproteins; Liver; Liver Cirrhosis; Liver diseases; Low-Density Lipoproteins; Malignant neoplasm of liver; Measurement; Mediating; Meta-Analysis; Metabolic; Metabolism; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Phenotype; Placebos; Play; Population; Portal Hypertension; Pravastatin; Prevention; Primary carcinoma of the liver cells; Proprotein Convertases; Prospective Studies; Prospective cohort; Prospective, cohort study; Randomized; Randomized, Controlled Trials; Reporting; Research; Resources; Retrospective Studies; Risk; Risk Factors; Role; Safety; Serum; Subtilisins; Testing; Translational Research; United States; Validation; biomarker discovery; chronic liver injury; clinical center; clinical predictors; clinically relevant; cohort; comorbidity; disorder risk; efficacy evaluation; endothelial dysfunction; fibrogenesis; high risk; improved; improved outcome; inflammatory marker; inhibitor; innovation; insight; lipid metabolism; liver allograft; liver transplantation; microbiome; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; predictive modeling; prevent; prospective; safety study; therapy outcome; virtual; virtual world

Project Summary/Abstract: Cirrhosis and its complications including hepatocellular carcinoma (HCC) are increasingly common causes of morbidity and mortality in the United States. The central hypotheses of this application are that (1) the creation of a prospective cohort study of patients with compensated cirrhosis will facilitate the generation of novel prediction models based on the clinical, behavioral, metabolic, and biomarker data we collect to predict clinical decompensation, (2) this cohort can validate and then be supplemented by a larger electronic health record (EHR)-based virtual cohort, the latter of which will enable validation of electronic cirrhosis phenotypes and subsequent analysis of real-world data on the safety and effectiveness of individual lipid-lowering agents on multiple outcomes among patients with cirrhosis and (3) long-term statin therapy will provide clinical benefits in preventing hepatic decompensation and HCC independent of its lipid lowering effect. To investigate these hypotheses, we propose unique approaches to both the cohort study and statin-based clinical trial for the Liver Cirrhosis Network (LCN). In Aim 1a, we will create a prospective cohort of highly phenotyped patients with compensated NASH, ALD, cholestatic and cryptogenic cirrhosis, in order to facilitate the interrogation of biospecimens, patient reported behaviors and outcomes, and clinical data for novel predictors of disease progression, and to understand through serum lipoproteins measurement the complex interaction between cirrhosis and lipid metabolism. In Aim 1b, we will create a large LCN-wide EHR-based virtual cohort of patients with compensated cirrhosis, prospectively validate electronic phenotypes for cirrhosis and its clinical complications with our in-person cohort, and evaluate the use, safety and effectiveness of different classes of lipid lowering medications upon outcomes in this large real-world virtual cohort. In Aim 2, we propose to study the safety and efficacy of statins in preventing clinical decompensation among patients with NAFLD or ALD cirrhosis while exploring the potential pleiotropic mechanisms of statins. In this trial, patients with and without an established non-hepatic indication for lipid lowering will be randomized to pravastatin v. alirocumab (stratum 1) or placebo (stratum 2), respectively. This innovative approach to the statin-based clinical trial will acknowledge the patient's baseline indication for lipid-lowering therapy, and offer an alternative lipid lowering pathway in PCSK9 inhibition, which has similar or greater LDL-lowering potency but lacks the pleotropic effects of statins, to allow for novel insights into mechanisms by which statins might impact outcomes independent of its effects on lipids. Throughout the cohort and interventional trials, we will study lipoprotein metabolism, inflammatory markers, and collect microbiome and biospecimens for future translational research to better understand the mechanisms behind disease progression in cirrhosis and for any potential impact of pravastatin and alirocumab on clinical outcomes. These innovative strategies therefore leverage both cohort and clinical trial designs to maximize the knowledge gained and improve clinical outcomes among patients with cirrhosis.

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