USC Cirrhosis Clinical Center

南加州大学肝硬化临床中心

• 批准号: 10704580
• 负责人: ANDREW Abba STOLZ
• 金额: $ 52.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704580
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Acculturation; Address; Adherence; Adult; Affect; Age; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Ancillary Study; Antiviral Therapy; Ascites; Asian; Asian population; Attention; Behavior; Biological; Black Populations; Body Weight decreased; California; Cardiovascular system; Caring; Cause of Death; Cessation of life; Characteristics; Child; Chronic; Cirrhosis; Cities; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collection; Compensation; County; Data; Development; Diabetes Mellitus; Educational Status; Endothelium; Etiology; Evaluation; Event; Fibrosis; Future; Goals; Health; Health Resources; Healthcare; Hemorrhage; Hepatic; Hepatic Encephalopathy; Hepatitis; Hepatitis B; Hepatitis C; Hepatotoxicity; Heterogeneity; Hispanic Populations; Human; Image; Incidence; Injury; Intervention Studies; Laboratories; Language; Life Style; Link; Liver; Liver diseases; Longitudinal cohort; Los Angeles; Measures; Minority Groups; Modeling; Morbidity - disease rate; Multicenter Studies; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Nature; Neighborhoods; Outcome; Participant; Pathway interactions; Patient-Centered Care; Patient-Focused Outcomes; Patients; Phospholipase; Physical activity; Placebo Control; Placebos; Population; Population Heterogeneity; Populations at Risk; Portal Hypertension; Poverty; Primary carcinoma of the liver cells; Process; Prospective cohort; Proteins; Public Health; Questionnaires; Radiology Specialty; Randomized; Randomized, Controlled Trials; Risk; Risk Reduction; Role; Safety; Specimen; Standardization; Subgroup; Therapeutic; Therapeutic Intervention; Underrepresented Minority; United States; Universities; Varicosity; Venous Pressure level; Viral hepatitis; Virus Diseases; alcohol abstinence; biobank; chronic liver disease; clinical center; clinically significant; cohort; community setting; contextual factors; dietary; drug induced liver injury; effective therapy; efficacy evaluation; ethnic diversity; experience; follow-up; genetic variant; health literacy; improved; improved outcome; inflammatory modulation; inhibitor; liver injury; mortality; multilevel analysis; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel drug class; patient oriented; phase 3 study; prevent; primary endpoint; prospective; racial diversity; racial population; response; rosuvastatin; safety net; sarcopenia; secondary endpoint; social; social determinants; social health determinants; sociodemographic factors; targeted treatment; translational study; transplant centers; treatment duration; trend

Cirrhosis is the 11th leading cause of death in the United States and its incidence is rising. Major causes of cirrhosis include chronic viral infections (hepatitis B and C), alcohol-associated cirrhosis (ALD) and non- alcoholic steatohepatitis (NASH). Stable compensated cirrhosis offers an opportunity to intervene to prevent progression to decompensation and thereby reduce liver-related deaths. Two stages of compensated cirrhosis are recognized; with stage 2 identified by the presence of clinically significant portal hypertension (CSPH, defined by hepatic venous pressure gradient of 10 mmHg or higher). Statins are a novel drug class for consideration in treatment of cirrhosis as preliminary data show reductions in both portal hypertension and improved survival and offer promise as a therapeutic intervention in stage 2 compensated cirrhosis. This multicenter study will establish a prospective cohort of 2000 patients with compensated cirrhosis and CSPH for longitudinal follow-up of changes in clinical, lifestyle, laboratory, and imaging characteristics combined with a rich biospecimen collection for future translational studies. Genetic variants, especially the role of patatin-like phospholipase domain-containing protein 3 (PNPLA-3), in cirrhosis progression and response to statin therapy. The primary goal of this longitudinal cohort is to characterize that natural history of compensated cirrhosis in a representative and contemporary population, and to refine the risk profiles for progression versus non- progression. Additionally, social determinants of health and their influence on healthcare engagement and promotion of healthy liver lifestyle will be examined, with further exploration of how these factors affects liver- related outcomes. Finally, a randomized, placebo-controlled phase 3 study of rosuvastatin will be conducted in 200 patients with compensated cirrhosis and CSPH due to treated hepatitis B or C, ALD or NASH. The treatment duration is 96 weeks with the primary endpoint being survival without decompensation. Secondary endpoints include liver-related mortality, cardiovascular events, diabetes and statin safety, including rates of hepatotoxicity and myotoxicity. The City of Angeles Clinical Center for Cirrhosis (CACC), located at the University of Southern California in Los Angeles, has a unique, ethnically diverse population, that well- represents the population experiencing rising rates of cirrhosis. Through this collaborative network, CACC will contribute to an: 1) enhanced patient-centered model of care; 2) build a rich biorepository to support ancillary and translational studies to improve our understanding of the pathobiology of cirrhosis progression and regression; and 3) conduct a rigorous clinical trial to define the role of statins, with particular attention to the role of PNPLA3 genetic variants on efficacy. Ultimately, the goal of these studies is to improve the clinical outcomes of patients with compensated cirrhosis, especially those from underrepresented minorities.

在美国，肝硬变是第11大死因，其发病率还在上升。主要原因是 肝硬变包括慢性病毒感染(乙肝和丙型肝炎)、酒精相关性肝硬变(ALD)和非酒精性肝炎 酒精性脂肪性肝炎(NASH)稳定的代偿性肝硬变提供了干预预防的机会 进展为失代偿，从而减少与肝脏相关的死亡。代偿性肝硬变的两个阶段 以临床上有意义的门脉高压(CSPH， 定义为肝静脉压力梯度为10毫米汞或更高)。他汀类药物是一种新型的治疗药物 考虑肝硬变的治疗，因为初步数据显示门静脉高压症和门静脉高压症都有所减少 改善存活率，并有望成为2期代偿性肝硬变的治疗干预手段。这 多中心研究将建立2000名代偿性肝硬变和CSPH患者的前瞻性队列 对临床、生活方式、实验室和影像特征变化的纵向随访，结合 丰富的生物标本收藏，为今后的翻译研究提供参考。遗传变异，特别是类Patatin的作用 磷脂酶结构域含蛋白3(PNPLA-3)，在肝硬变进展和他汀类药物治疗中的反应。 这一纵向队列主要目的是描述代偿性肝硬变患者的自然病史。 有代表性的和当代的人群，并完善进展与非进展的风险概况 进步。此外，健康的社会决定因素及其对医疗保健参与度和 课程将探讨如何推广健康的肝脏生活方式，并进一步探讨这些因素如何影响肝脏- 相关结果。最后，瑞舒伐他汀的随机、安慰剂对照的第三阶段研究将在#年进行。 200例因治疗乙型或丙型肝炎、ALD或NASH而导致的代偿性肝硬变和CSPH。这个 治疗持续时间为96周，主要终点是存活而不失代偿。次要的 终点包括与肝脏相关的死亡率、心血管事件、糖尿病和他汀类药物的安全性，包括 肝脏毒性和肌肉毒性。洛杉矶市肝硬化临床中心(CACC)，位于 位于洛杉矶的南加州大学拥有独特的、种族多元化的人口，那就是- 代表经历肝硬化率上升的人群。通过这个协作网络，CACC将 有助于：1)增强以患者为中心的护理模式；2)构建丰富的生物信息库以支持 辅助和翻译研究以提高我们对肝硬变进展的病理生物学的了解 和回归；以及3)进行严格的临床试验，以确定他汀类药物的作用，并特别注意 PNPLA3基因变异对疗效的作用。最终，这些研究的目标是改善 代偿性肝硬变患者的临床结局，特别是那些代表性不足的患者 少数族裔。