Liver Cirrhosis Network: Clinical Research Centers

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）、酒精性肝炎（NASH）、酒精性肝炎（NASH）和肝硬化相关。 引起的肝病（ALD）和艾滋病毒感染者。肝硬化进展为肝脏相关临床 LACE事件（LACE）和死亡与多种可能是病因学的全身和肝脏因素相关- 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- 进展到成果。这限制了用于风险分层的非侵入性工具的合理开发， 疾病监测目的以及对结果的发展进行整体建模的能力。有 也没有确定的病因不可知的方法来降低结局和死亡的风险。这项提案，在 对RFA-DK-20-003的回应，通过两个具体目标解决这些未满足的需求：目标1： 在不同病因的肝硬化患者中进行的前瞻性、多中心、观察性研究， 进行新的机制和治疗研究的基础。代偿性肝硬化患者 将招募包括NASH、ALD伴和不伴HIV在内的不同病因，并进行前瞻性随访， 方案驱动的数据和生物样本收集。将由预先指定的 裁决过程。通过与外部合作伙伴的合作，我们将评估几个有前途的工具， (e.g.脾硬度测量）、循环生物标志物（E133 -6，ELF测试）和机器学习 获得关于纤维化的新见解的方法，驱动结果的因素和模型结果。队列 数据和生物样本将进一步支持对纤维化驱动因素和结果的机制研究。目标二： 进行一项多中心、前瞻性、随机、双盲、安慰剂对照的临床试验， 阿托伐他汀（10 mg/天× 2年）在代偿性肝硬化患者中的临床应用。患者 根据静脉曲张和CTP评分（5或6分）分层的不同病因的代偿性肝硬化患者将入选。审判 设计使用FDA提出的被估量框架（ICH E9 R1）。主要终点捕获获益 从患者的角度来看，定义为无LACE或主要不良心脏事件或需要 因毒性而停药。主要分析将比较符合以下条件的患者比例： 主要终点。获益的次要分析是临床结局的至事件发生时间分析。几 提出了跟踪安全性和降低研究风险的措施。使用最新技术水平进行获益-风险分析 方法提出。总之，它们将提供关于阿托伐他汀改善心血管疾病的效用的可靠信息。 代偿性肝硬化的结局。这些研究的可行性得到了广泛和有力的支持 网络，一个强大的远程医疗计划，肝病和研究基础设施。这些研究将有一个 主要的积极影响：（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）模拟临床结局风险，为未来的监测策略提供信息， 和（5）提供一种治疗以减缓这种进展，从而提供一种减轻肝硬化负担的方法。

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.