San Diego Cirrhosis Clinical Research Network

项目总结 此申请是对RFA-DK-20-003的响应，这是与客观存在的有限竞争机会 建立肝硬变网络(LCN)。在过去的十年中，肝硬变的患病率翻了一番，而且 现在是美国第11大死因。与肝硬变相关的死亡人数预计为 到2030年，NASH预计将超过丙型肝炎病毒，成为肝脏移植的主要原因。严格的限制 关于肝硬变患者每年进行肝移植的次数和预期增加 人口迫切需要更好地了解肝硬化死亡率的预测因素，并制定有效的 治疗肝硬变的疗法。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患肝癌的风险 和肝硬变患者的失代偿。在他汀类药物中，阿托伐他汀等亲脂性他汀类药物显示 对肝癌发生最大的化学预防作用。阿托伐他汀与剂量依赖相关 减少丙型肝炎患者的肝硬变发生率。支持他汀类药物用于肝硬变的数据前景看好，但规模更大， 需要随机对照试验(RCT)来确定它们是否可以被常规推荐。至 针对肝硬变患者人群的需求，本研究计划提出了以下目标：目标1： 对肝硬变患者进行前瞻性、纵向、多中心、多种族队列研究。 在西班牙裔男性中，肝硬变是导致死亡的第六大原因。为了解决这种健康差距，我们将测试 与西班牙裔肝硬变患者相比，西班牙裔肝硬变患者肝脏失代偿风险更高的假说 非西班牙裔美国人。我们将建立和监测因多种原因导致的肝硬变患者队列。 主要终点包括(A)肝脏失代偿的复合终点，(B)肝移植，或(C) 全因死亡。辅助研究将调查非侵入性成像生物标志物之间的关系， 肝硬变遗传风险评分和失代偿风险。在我们之前工作的基础上，我们还将确定 可以预测失代偿风险的微生物组特征。目标2：阶段2，多中心，双盲， 安慰剂对照、随机对照试验评价阿托伐他汀20 mg治疗慢性阻塞性肺疾病的疗效和安全性 代偿性肝硬变。目的是验证阿托伐他汀比安慰剂更有效的假设 降低肝硬变患者失代偿风险、全因死亡率和其他与肝脏相关的临床结果 病人。主要结果衡量标准将是首次发生下列任何已判定事件的时间： 全因死亡率，MELD评分≥15，肝移植，腹水需要医疗干预，住院治疗 静脉曲张出血、肝性脑病、自发性细菌性腹膜炎的发病，以及 肝细胞癌。次要结果包括阿托伐他汀的安全性、纤维化的减少 通过NITS和成像生物标记物，以及主要不良心血管事件。探索性分析将调查 治疗反应与(A)增量MRE和VCTE、(B)遗传危险因素和(C)变化之间的关系 在肠道微生物群中。

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.