Liver Cirrhosis Network: Clinical Research Centers

肝硬化网络：临床研究中心

• 批准号: 10308126
• 负责人: Jasmohan S Bajaj
• 金额: $ 35.85万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308126
• 关键词: Address; Alcoholic Liver Diseases; Ancillary Study; Anti-Inflammatory Agents; Ascites; Automobile Driving; Benefits and Risks; Biological Specimen Banks; Biology; Cardiac; Cardiovascular system; Cataloging; Cessation of life; Child; Cholesterol; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Collaborations; Collection; Controlled Clinical Trials; Data; Development; Disease; Disease Progression; Disease model; Dose; Double-Blind Method; Encephalopathies; Enrollment; Etiology; Event; Feasibility Studies; Fibrosis; Foundations; Future; HIV; Healthcare; Hemorrhage; Hepatic; Image; Individual; Infrastructure; Knowledge; Laboratories; Lead; Letters; Liver; Liver Cirrhosis; Liver diseases; Longitudinal cohort; Machine Learning; Measurement; Measures; Medical center; Methods; Mission; Modeling; Monitor; Multicenter Studies; Multicenter Trials; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Outcome; Participant; Patients; Pharmaceutical Preparations; Phase; Placebos; Population; Process; Property; Protocols documentation; Randomized; Recording of previous events; Reproducibility; Research Infrastructure; Risk; Risk-Benefit Assessment; Safety; Sample Size; Sampling; Severities; Special Population; Specific qualifier value; Spleen; Technology; Telemedicine; Testing; Therapeutic Studies; Time; Toxic effect; Translational Research; Varicosity; Viral hepatitis; adjudication; atorvastatin; base; care burden; chronic liver disease; circulating biomarkers; cohort; data acquisition; drug withdrawal; efficacy evaluation; experience; follow-up; improved outcome; innovation; insight; liver injury; longitudinal database; meetings; model development; nonalcoholic steatohepatitis; novel; prevent; primary endpoint; programs; prospective; public-private partnership; recruit; response; risk stratification; secondary analysis; specific biomarkers; tool; trial design

The population burden of cirrhosis is rising especially related to nonalcoholic steatohepatitis (NASH), alcohol- induced liver disease (ALD) and in those living with HIV. The progression of cirrhosis to liver-associated clinical events (LACE) and death is related to a diverse set of systemic and hepatic factors which may be etiology- specific or agnostic. There remain gaps in knowledge in assessing how these factors interact to cause cirrhosis- progression to outcomes. This limits rational development of non-invasive tools for risk-stratification and disease-monitoring purposes as well as the ability to holistically model the development of outcomes. There is also no established etiology-agnostic approach to reduce the risk of outcomes and death. This proposal, in response to RFA-DK-20-003, addresses these unmet needs with two specific aims: Aim 1: To conduct a prospective, multicenter, observational study of patients with cirrhosis of varying etiology that serves as the foundation for conducting novel mechanistic and therapeutic studies. Patients with compensated cirrhosis of varying etiology inclusive of NASH, ALD with and without HIV will be enrolled and followed prospectively with protocol-driven data and bio-sample collection. Outcomes will be assessed prospectively by a pre-specified adjudication process. Through collaboration with external partners, we will evaluate several promising tools (e.g. spleen-stiffness measurement), circulating biomarkers (PROC3-6, ELF test) and machine-learned approaches to obtain novel insights on fibrosis, factors driving outcomes and to model outcomes. The cohort data and bio-samples will further support mechanistic studies of factors driving fibrosis and outcomes. Aim 2: To perform a multi-center prospective randomized, double-blind placebo-controlled clinical trial to evaluate the clinical utility of atorvastatin (10 mg/day x 2 yrs) in patients with compensated cirrhosis. Patients with compensated cirrhosis of varying etiology, stratified by varices and CTP score (5 or 6) will be enrolled. The trial design uses the estimand framework proposed by the FDA (ICH E9 R1). The primary endpoint captures benefit from a patient-perspective and is defined by survival without LACE or major adverse cardiac event or need for drug withdrawal for toxicity. The primary analysis will be a comparison of proportions of patients meeting the primary endpoint. The secondary analysis of benefit is a time-to-event analysis of clinical outcomes. Several measures to track safety and de-risk the study are proposed. A benefit-risk analyses using state of the art approach is proposed. Together, they will provide robust information on the utility of atorvastatin to improve outcomes in compensated cirrhosis. The feasibility of the studies is supported by a strong and extensive referral network, a robust tele-medicine program for liver disease and research infrastructure. The studies will have a major positive impact by: (1) providing robust outcomes data, (2) supporting mechanistic studies, (3) use of innovations to refine application of NITs, (4) model clinical outcome risk to inform future monitoring strategies, and (5) provide a treatment to slow this progression, thereby providing a way to reduce the burden of cirrhosis.

肝硬化的人口负担正在上升，特别是与非酒精性脂肪性肝炎（NASH）、酒精相关的疾病有关。 诱发性肝病（ALD）和艾滋病毒感染者。肝硬化进展为肝相关临床 事件（LACE）和死亡与多种全身和肝脏因素有关，其病因可能是- 具体的或不可知的。在评估这些因素如何相互作用导致肝硬化方面仍然存在知识空白。 进展到结果。这限制了风险分层和非侵入性工具的合理开发 疾病监测目的以及对结果发展进行整体建模的能力。有 也没有既定的病因不可知方法来降低结果和死亡的风险。这项提议，在 对 RFA-DK-20-003 的回应，解决了这些未满足的需求，有两个具体目标： 目标 1：开展 对不同病因的肝硬化患者进行的前瞻性、多中心、观察性研究 为进行新的机制和治疗研究奠定了基础。代偿性肝硬化患者 不同的病因包括 NASH、ALD（伴或不伴 HIV）将被纳入并进行前瞻性随访 协议驱动的数据和生物样本收集。结果将由预先指定的人员进行前瞻性评估 裁决过程。通过与外部合作伙伴的合作，我们将评估几种有前途的工具 （例如脾硬度测量）、循环生物标志物（PROC3-6、ELF 测试）和机器学习 获得关于纤维化、驱动结果的因素和结果建模的新见解的方法。队列 数据和生物样本将进一步支持驱动纤维化因素和结果的机制研究。目标 2： 进行多中心前瞻性随机、双盲安慰剂对照临床试验来评估 阿托伐他汀（10 毫克/天 x 2 年）在代偿性肝硬化患者中的临床效用。患者患有 将纳入不同病因的代偿性肝硬化，按静脉曲张和 CTP 评分（5 或 6）分层。审判 设计使用 FDA (ICH E9 R1) 提出的估计框架。主要终点获得益处 从患者的角度来看，定义为没有 LACE 或重大不良心脏事件或需要治疗的生存期 因毒性而停药。主要分析将比较满足以下条件的患者比例 主要终点。效益的二次分析是临床结果的时间到事件分析。一些 提出了跟踪安全性和降低研究风险的措施。使用最先进的技术进行效益-风险分析 提出了方法。他们将共同提供有关阿托伐他汀的实用性的可靠信息，以改善 代偿性肝硬化的结果。研究的可行性得到了强有力和广泛的推荐的支持 网络，一个强大的肝病远程医疗计划和研究基础设施。这些研究将有一个 通过以下方式产生重大积极影响：(1) 提供可靠的结果数据，(2) 支持机制研究，(3) 使用 改进 NIT 应用的创新，(4) 建立临床结果风险模型，为未来的监测策略提供信息， (5)提供一种治疗方法来减缓这种进展，从而提供一种减轻肝硬化负担的方法。