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.

项目摘要/摘要： 肝硬化及其并发症，包括肝细胞癌（HCC）是越来越普遍的原因 美国的发病率和死亡率。该应用程序的中心假设是（1）创建 对肝硬化的患者的一项前瞻性队列研究将有助于产生新的新型 我们收集的基于临床，行为，代谢和生物标志物数据的预测模型，以预测临床 代偿作用，（2）该队列可以验证，然后通过较大的电子健康记录补充 （EHR）基于的虚拟队列，后者将验证电子肝硬化表型和 随后分析有关单个降低脂质剂在安全性和有效性上的现实数据的分析 肝硬化患者和（3）长期他汀类药物疗法的多种结果将在 防止肝功能不全和HCC独立于其脂质降低效果。调查这些 假设，我们提出了肝脏研究和基于他汀类药物的临床试验的独特方法 肝硬化网络（LCN）。在AIM 1A中，我们将创建一个前瞻性的高度表型患者 为了促进审讯 生物测量，患者报告的行为和结果以及疾病的新预测指标的临床数据 进展，并通过血清脂蛋白测量来理解复杂的相互作用 肝硬化和脂质代谢。在AIM 1B中，我们将创建一个大的LCN EHR基于EHR的虚拟队列 与肝硬化的补偿，前瞻性验证电子表型用于肝硬化及其临床 我们的面对面队列的并发症，并评估不同类别的使用，安全性和有效性 在这个大型现实世界虚拟队列中，脂质降低药物。在AIM 2中，我们建议学习 他汀类药物在预防NAFLD或ALD患者临床代偿方面的安全性和功效 肝硬化，同时探索他汀类药物的潜在多效机制。在此试验中，有和没有的患者 已建立的脂质降低的非肝脏指示将被随机分为Pravastatinv。Alirocumab（Stratum 1） 或安慰剂（分层2）。这种基于他汀类药物的临床试验的创新方法将确认 患者的降脂疗法的基线指示，并提供替代的脂质降低途径 PCSK9抑制作用，具有相似或更大的LDL效力，但缺乏他汀类药物的多余作用， 为了对他汀类药物可能影响结果独立于其影响的结局提供新的见解 在脂质上。在整个队列和介入试验中，我们将研究脂蛋白代谢，炎症 标记，并收集微生物组和生物测量，以供未来的翻译研究，以更好地了解 肝硬化的疾病进展背后的机制以及pravastatin和alirocumab的任何潜在影响 关于临床结果。因此，这些创新策略利用了队列和临床试验设计 最大化获得的知识并改善肝硬化患者的临床结果。