San Diego Cirrhosis Clinical Research Network

圣地亚哥肝硬化临床研究网络

基本信息

批准号：
10700072
负责人：
ROHIT LOOMBA
金额：
$ 50.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-09 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700072
关键词：
Address Alcoholic Liver Diseases Ancillary Study Antineoplastic Agents Area Ascites California Cardiovascular system Cause of Death Cessation of life Chemopreventive Agent Chronic Hepatitis C Cirrhosis Clinical Clinical Research Clinical Trials Design Cohort Studies Compensation Consent County Data Development Diagnosis Disease Disease Progression Dose Double-Blind Method Etiology Event Fibrosis Future General Population Genetic Risk HCV Liver Disease HIV Hemorrhage Hepatic Hepatic Encephalopathy Hepatitis B Virus Hepatitis C virus Hepatology Hepatorenal Syndrome Hispanic Hispanic Populations Hospitalization Institution Intervention Liver Liver Cirrhosis Malignant neoplasm of liver Measures Medical Meta-Analysis Monitor Multi-Institutional Clinical Trial Natural History Not Hispanic or Latino Outcome Outcome Measure Participant Patient Recruitments Patients Peritonitis Pharmacogenetics Phase Placebo Control Placebos Positioning Attribute Prevalence Primary carcinoma of the liver cells Property Protocols documentation Randomized, Controlled Trials Recommendation Research Research Infrastructure Risk Risk Reduction Safety Site Testing Time United States United States National Institutes of Health Virus Diseases Work adjudication atorvastatin clinical infrastructure cohort effective therapy efficacy evaluation genetic risk factor gut microbiome health disparity high risk imaging biomarker lipophilicity liver stiffness liver transplantation men microbiome microbiome signature mortality mortality risk multi-ethnic non-invasive imaging nonalcoholic steatohepatitis novel therapeutics patient population pleiotropism primary endpoint primary outcome prospective randomized placebo controlled trial recruit response secondary outcome treatment response

项目摘要

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.

项目概要此应用程序是为了响应 RFA-DK-20-003，这是一个有限的竞争机会，其目标是肝硬化网络 (LCN) 的建立在过去十年中肝硬化患病率翻了一番。目前已成为美国第 11 大死因，预计与肝硬化相关的死亡人数将达到到 2030 年，NASH 预计将超过 HCV，成为肝移植严重限制的主要原因。每年进行的肝移植数量以及肝硬化患者的预期增长人们迫切需要更好地了解肝硬化死亡率的预测因素并提高其有效性我们小组和其他人的研究表明他汀类药物可以降低未来患 HCC 的风险。在他汀类药物中，阿托伐他汀等亲脂性他汀类药物已显示出肝硬化患者的代偿失调。阿托伐他汀对 HCC 发生的最大化学预防作用与剂量依赖性相关。支持他汀类药物治疗肝硬化的数据显示，HCV 患者肝硬化的发生率有所下降，但前景广阔。需要随机对照试验（RCT）来确定是否可以常规推荐它们。为了满足肝硬化患者群体的需求，本研究计划提出以下目标：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。为了解决这一健康差异，我们将进行测试。与西班牙裔肝硬化患者相比，西班牙裔肝硬化患者发生肝功能失代偿的风险更高的假设我们将建立并监测一组因多种病因而患有肝硬化的患者。主要终点包括（a）肝失代偿的复合终点，（b）肝移植，或（c）全因死亡率的辅助研究将调查非侵入性成像生物标志物之间的关联，继我们之前的工作之后，我们还将确定肝硬化遗传风险评分和失代偿风险。可以预测失代偿风险的微生物组特征目标 2：第 2 阶段，多中心，双盲，安慰剂对照、随机对照试验评估阿托伐他汀 20 mg 在患有以下疾病的受试者中的疗效和安全性目的是检验阿托伐他汀比安慰剂更有效的假设。降低肝硬化失代偿风险、全因死亡率和其他与肝脏相关的临床结果主要结果指标是首次发生以下任何判定事件的时间：全因死亡率、MELD 评分≥ 15、肝移植、需要医疗干预的腹水、住院治疗静脉曲张出血、肝性脑病、自发性细菌性腹膜炎以及发展为次要结果包括阿托伐他汀的安全性、纤维化的减少（如测量）。通过 NIT 和成像生物标志物，以及主要不良心血管事件进行探索性分析。治疗反应与 (a) delta MRE 和 VCTE、(b) 遗传风险因素以及 (c) 变化之间的关联在肠道微生物组中。