Liver Cirrhosis Network: Clinical Research Centers

肝硬变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- 诱发肝病(ALD)和艾滋病毒携带者。肝炎后肝硬变的临床进展 事件(蕾丝)和死亡与一系列不同的系统和肝脏因素有关，这些因素可能是病因- 具体的或不可知论者。在评估这些因素如何相互作用导致肝硬变方面仍然存在知识空白- 向结果进发。这限制了非侵入性工具的合理开发，用于风险分层和 疾病监测目的以及对结果的发展进行整体建模的能力。的确有 也没有既定的病因学-不可知论方法来降低结局和死亡的风险。这项建议，在 对RFA-DK-20-003的回应，以两个具体目标解决这些未得到满足的需求：目标1：开展 对不同病因的肝硬变患者进行前瞻性、多中心、观察性研究 进行新的机制和治疗研究的基础。代偿性肝硬变患者临床分析 不同的病因，包括NASH，ALD伴和不伴HIV将被登记，并前瞻性地跟随 协议驱动的数据和生物样本收集。结果将通过预先指定的 裁决程序。通过与外部合作伙伴的合作，我们将评估几个有前景的工具 (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、驱动结果的因素和建立结果模型的新见解的方法。这群人 数据和生物样本将进一步支持推动纤维化因素和结果的机制研究。目标2： 进行一项多中心前瞻性、随机、双盲、安慰剂对照的临床试验，以评估 阿托伐他汀(10 mg/d×2年)在代偿性肝硬变患者中的临床应用。患有疾病的患者 根据静脉曲张和CTP评分(5或6)分层的不同病因的代偿性肝硬变将纳入研究。这场审判 设计使用FDA提出的评估和框架(ICH E9 R1)。主端点获得优势 从患者的角度来看，其定义为没有花边或主要不良心脏事件或需要 因中毒而停药。主要的分析将是比较符合以下条件的患者比例 主端点。收益的二次分析是对临床结果的时间-事件分析。几个 提出了跟踪安全和降低研究风险的措施。利用最新技术进行收益-风险分析 提出了解决这一问题的方法。它们将共同提供有关阿托伐他汀的效用的可靠信息，以改善 代偿性肝硬变的转归。研究的可行性得到了强有力和广泛的转介的支持 网络，一个强大的肝脏疾病和研究基础设施的远程医疗计划。这些研究将有一个 主要的积极影响是：(1)提供可靠的成果数据，(2)支持机制研究，(3)使用 改进NITS应用的创新；(4)建立临床结果风险模型，为未来的监测战略提供信息； 以及(5)提供一种减缓这一进展的治疗方法，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.