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: 10311423
• 负责人: ROBERT S BROWN
• 金额: $ 35.33万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311423
• 关键词: Alcohols; Behavioral; Biological Markers; Cessation of life; Cirrhosis; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cohort Studies; Complex; Cryptogenic cirrhosis; Data; Data Set; Development; Disease Progression; Effectiveness; Electronic Health Record; Etiology; Fatty acid glycerol esters; Future; Generations; Health; Hepatic; Hepatotoxicity; Human; Incidence; Individual; Inflammation; Intervention; Intervention Trial; Knowledge; Lead; 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; base; behavioral outcome; biomarker discovery; chronic liver injury; clinical center; clinical predictors; clinically relevant; cohort; comorbidity; disorder risk; endothelial dysfunction; fibrogenesis; high risk; improved; improved outcome; inflammatory marker; inhibitor/antagonist; 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.

项目概要/摘要： 肝硬化及其并发症，包括肝细胞癌（HCC），是越来越常见的原因， 美国的发病率和死亡率。本申请的中心假设是：（1）创造 代偿性肝硬化患者的前瞻性队列研究将有助于产生新的 基于我们收集的临床、行为、代谢和生物标志物数据的预测模型， 失代偿，（2）该队列可以验证，然后通过更大的电子健康记录进行补充 （EHR）为基础的虚拟队列，后者将使电子肝硬化表型的验证， 随后分析了关于个体降脂药对以下疾病的安全性和有效性的真实世界数据： 肝硬化患者的多种结局和（3）长期他汀类药物治疗将在以下方面提供临床益处： 预防肝代偿失调和HCC，而不依赖于其降脂作用。调查这些 假设，我们提出了独特的方法，既队列研究和他汀类药物为基础的临床试验的肝脏 肝硬化网络（LCN）。在目标1a中，我们将创建一个前瞻性队列，其中包括具有以下特征的高表型患者： 代偿性NASH、ALD、胆汁淤积性和隐源性肝硬化，以便于询问 生物样本、患者报告的行为和结局以及疾病新预测因子的临床数据 进展，并了解通过血清脂蛋白测量之间的复杂相互作用， 肝硬化和脂质代谢。在目标1b中，我们将创建一个大型的LCN范围内基于EHR的虚拟患者队列 对于代偿性肝硬化，前瞻性验证肝硬化及其临床的电子表型 并发症与我们的人队列，并评估不同类别的使用，安全性和有效性， 在这个大型的真实世界虚拟队列中，降脂药物对结果的影响。在目标2中，我们建议研究 他汀类药物预防NAFLD或ALD患者临床失代偿的安全性和有效性 肝硬化，同时探索他汀类药物的潜在多效性机制。在这项试验中， 已确定的非肝脏降脂适应症将随机分配至普伐他汀与alirocumab组（第1层） 或安慰剂（层2）。这种基于他汀类药物的临床试验的创新方法将承认 患者的基线降脂治疗适应症，并提供替代降脂途径， PCSK 9抑制，具有相似或更高的LDL降低效力，但缺乏他汀类药物的多效性作用， 允许对他汀类药物可能独立于其作用影响结果的机制进行新的见解 对脂质的影响在整个队列和干预性试验中，我们将研究脂蛋白代谢、炎症反应、 标记，并收集微生物组和生物标本，用于未来的转化研究，以更好地了解 肝硬化疾病进展背后的机制以及普伐他汀和alirocumab的任何潜在影响 临床结果。因此，这些创新策略利用队列和临床试验设计， 最大限度地获得知识，改善肝硬化患者的临床结局。