Liver Cirrhosis Network: Clinical Research Centers

肝硬化网络：临床研究中心

• 批准号: 10700058
• 负责人: Jasmohan S Bajaj
• 金额: $ 30.62万
• 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/10700058
• 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; Compensation; 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; Letters; Liver; Liver Cirrhosis; Liver diseases; Longitudinal cohort; Machine Learning; Measurement; Measures; Medical center; 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 Reduction; 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; machine learning method; meetings; model development; nonalcoholic steatohepatitis; novel; prevent; primary endpoint; programs; progression risk; 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）有关