Liver Cirrhosis Network: Clinical Research Centers

肝硬化网络：临床研究中心

• 批准号: 10487561
• 负责人: Jasmohan S Bajaj
• 金额: $ 37.54万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487561
• 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; Placebo Control; 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; end stage liver disease; 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增加，尤其与非酒精性脂肪性肝炎（NASH），酒精 - 诱发肝病（ALD）和患有艾滋病毒的患者。肝硬化向肝相关的临床发展 事件（蕾丝）和死亡与可能是病因的各种系统性和肝因子有关 特定或不可知论。在评估这些因素如何相互作用以引起肝硬化 - 进展到结果。这限制了非侵入性工具的合理发展，以进行风险分层和 疾病监测的目的以及整体建模结果发展的能力。有 也没有建立的病因学方法来降低结局和死亡的风险。该提议，在 对RFA-DK-20-003的响应，以两个具体的目的解决了这些未满足的需求：目标1：进行 肝硬化患者的前瞻性，多中心，观察性研究，病因不同 进行新的机械和治疗研究基金会。肝硬化的患者 包括纳什（Nash），ALD的不同病因将被纳入和没有艾滋病毒 协议驱动的数据和生物样本集合。结果将被预先指定的前瞻性评估 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，脾脏态度测量），循环生物标志物（PROC3-6，ELF测试）和机器学习 获得有关纤维化的新见解的方法，因素推动结果和模拟结果。队列 数据和生物样本将进一步支持驱动纤维化和结果的因素的机械研究。目标2： 进行多中心的前瞻性随机，双盲安慰剂对照临床试验以评估 阿托伐他汀（10 mg/x 2年）在肝硬化患者中的临床实用性。患者 将纳入各种病因的补偿性肝硬化，按静脉曲张和CTP评分（5或6）分层。试验 设计使用FDA提出的估算和框架（ICH E9 R1）。主要终点捕获了好处 从患者角度来看，由无蕾丝或重大不良心脏事件或需要的生存定义 毒性提取药物。主要分析将是对满足患者比例的比较 主要终点。福利的次要分析是对临床结果的事实分析。一些 提出了跟踪安全性和降风险的措施。使用最新状态进行福利风险分析 提出了方法。他们将共同提供有关Atorvastatin效用的强大信息，以改善 补偿肝硬化的结果。研究的可行性得到了强烈而广泛的推荐的支持 Network是一项强大的肝病和研究基础设施的远程医学计划。研究将有一个 主要的积极影响：（1）提供可靠的结果数据，（2）支持机理研究，（3）使用 （4）建模临床结果风险以告知未来监测策略， （5）提供了减慢这种进展的治疗方法，从而提供了减轻肝硬化负担的方法。