San Diego Cirrhosis Clinical Research Network

项目摘要 本申请是对RFA-DK-20-003的回应，这是一个有限的竞争机会，目的是 肝硬化网络（LCN）肝硬化的患病率在过去十年中翻了一番， 现在是美国第11大死因预计与糖尿病有关的死亡人数将 到2030年，NASH预计将超过HCV成为肝移植的主要原因。严重限制 每年进行的肝移植数量以及肝硬化患者的预期增加 因此，迫切需要更好地了解肝硬化死亡率的预测因素， 治疗肝硬化的方法我们小组和其他人的研究表明他汀类药物可能会降低未来肝癌的风险 肝硬化患者的失代偿。在他汀类药物中，亲脂性他汀类药物如阿托伐他汀已经显示出 对HCC发生的最大化学预防作用。阿托伐他汀与剂量依赖性 降低HCV患者的肝硬化发病率。支持他汀类药物用于肝硬化的数据是有希望的，但更大， 需要随机对照试验（RCT）来确定是否可以常规推荐。到 为了满足肝硬化患者人群的需求，本研究计划提出了以下目标：目标1： 对肝硬化患者进行前瞻性、纵向、多中心、多种族队列研究。 在西班牙裔男性中，肝硬化是第六大死亡原因。为了解决这种健康差距，我们将测试 假设西班牙裔肝硬化患者的肝失代偿风险高于 非西班牙裔。我们将建立并监测一个由多种病因引起的肝硬化患者队列。 主要终点包括（a）肝功能失代偿的复合终点，（B）肝移植，或（c） 全因死亡率辅助研究将调查非侵入性成像生物标志物之间的关联， 肝硬化遗传风险评分和失代偿风险。在我们以往工作的基础上，我们还将确定 一个可以预测失代偿风险的微生物组特征。目的2：II期、多中心、双盲， 安慰剂对照RCT，评价阿托伐他汀20 mg在以下受试者中的疗效和安全性： 代偿性肝硬化目的是检验阿托伐他汀比安慰剂更有效的假设 降低肝硬化失代偿、全因死亡率和其他肝脏相关临床结局的风险 患者主要结局指标为至首次发生以下任何裁定事件的时间： 全因死亡率、MELD评分≥ 15、肝移植、需要医疗干预的腹水、 发生静脉曲张出血、肝性脑病、自发性细菌性腹膜炎，以及 肝细胞癌次要结局包括阿托伐他汀的安全性， 通过NIT和成像生物标志物，以及主要不良心血管事件。探索性分析将调查 治疗应答与（a）Δ MRE和VCTE，（B）遗传风险因素和（c）变化之间的相关性 在肠道微生物组中。

PROJECT SUMMARY This application is in response to RFA-DK-20-003, which is a limited competition opportunity with the objective of establishing the Liver Cirrhosis Network (LCN). Cirrhosis has doubled in prevalence in the last decade and is now the 11th leading cause of death in the United States. The number of cirrhosis-related deaths is projected to triple by 2030, with NASH projected to overtake HCV as the leading cause of liver transplantations. Severe limits on the number of liver transplantations performed each year and anticipated increases in the cirrhosis patient population create an urgent need to better understand predictors of mortality in cirrhosis and develop effective therapies to treat cirrhosis. Studies from our group and others suggest statins may reduce future risk of HCC and decompensation in patients with cirrhosis. Among statins, lipophilic statins such as atorvastatin have shown the greatest chemopreventive effects against HCC occurrence. Atorvastatin is associated with dose-dependent reduction in incident cirrhosis in HCV patients. Data supporting statin use for cirrhosis are promising, but larger, randomized controlled trials (RCT) are needed to determine whether they may be routinely recommended. To address the needs of the cirrhosis patient population, this research plan proposes the following aims: Aim 1: To conduct a prospective, longitudinal, multicenter, multi-ethnic cohort study of patients with cirrhosis. Among Hispanic men, cirrhosis is the 6th leading cause of mortality. To address this health disparity, we will test the hypothesis that Hispanic patients with cirrhosis are at higher risk for hepatic decompensation compared to non-Hispanics. We will establish and monitor a cohort of patients who have cirrhosis due to multiple etiologies. Primary endpoints include (a) a composite endpoint of hepatic decompensation, (b) liver transplantation, or (c) all–cause mortality. Ancillary studies will investigate associations between non-invasive imaging biomarkers, cirrhosis genetic risk score, and risk of decompensation. Following up on our previous work, we will also identify a microbiome signature that may predict decompensation risk. Aim 2: Phase 2, multi-center, double-blind, placebo-controlled, RCT evaluating efficacy and safety of atorvastatin 20 mg in subjects with compensated cirrhosis. The objective is to test the hypothesis that atorvastatin is more effective than placebo in reducing risk of decompensation, all-cause mortality and other liver-related clinical outcomes in cirrhosis patients. Primary outcome measure will be time to the first occurrence of any of the following adjudicated events: all-cause mortality, MELD score ≥ 15, liver transplant, ascites requiring medical intervention, hospitalization for onset of variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and development of hepatocellular carcinoma. Secondary outcomes include safety of atorvastatin, decrease in fibrosis, as measured by NITs and imaging biomarkers, and major adverse cardiovascular events. Exploratory analyses will investigate associations between treatment response and (a) delta MRE and VCTE, (b) genetic risk factors, and (c) changes in the gut microbiome.