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Alcoholic Hepatitis Network 3/9 University of Louisville

酒精性肝炎网络 3/9 路易斯维尔大学

基本信息

批准号：
10434741
负责人：
CRAIG J. MCCLAIN
金额：
$ 34.96万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434741
关键词：
Adrenal Cortex Hormones Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Biological Specimen Banks Clinical Clinical Research Clinical Trials Clinical Trials Design Collection Conduct Clinical Trials Consumption Data Data Coordinating Center Data Set Databases Development Disease Economic Burden Educational workshop Eligibility Determination FDA approved Foundations Funding Future Goals Granulocyte Colony-Stimulating Factor Hepatitis B Infection Inflammasome Inflammation Informatics Institution Interleukin-1 Receptors Interleukin-1 beta Label Laboratories Life Light Literature Liver Liver diseases Medical Mission Morbidity - disease rate National Institute on Alcohol Abuse and Alcoholism Observational Study Oral cavity Outcome Pathogenesis Patient Care Patient Recruitments Patients Pentoxifylline Pharmaceutical Preparations Phase Pilot Projects Positioning Attribute Predisposition Prednisone Public Health Randomized Recording of previous events Research Design Research Personnel Resources Role Sampling Severities Systems Biology Testing Therapeutic Therapeutic Studies Translational Research Universities Validation Work Zinc active method anakinra antagonist base catalyst clinical center drug testing effective therapy efficacy trial end stage liver disease evidence base improved insight interest liver injury longitudinal database meetings mortality new therapeutic target novel primary endpoint prospective receptor research study secondary endpoint standard of care targeted treatment therapeutic development therapeutically effective translational study treatment arm

项目摘要

ABSTRACT Alcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity of effective therapeutics. This application represents a coordinated submission of several NIAAA-funded consortia that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively, the network will synergize efforts and expertise to better understand AH and develop novel effective and safe therapies for severe AH. Buttressing that goal, the overarching aims of this new consortium are to: 1) perform studies to better understand the pathogenesis and main determinants of outcomes, particularly in severe AH; 2) identify novel targets for therapy of AH, and 3) perform phase 2B studies of compounds that are already FDA approved and available and can be repurposed as safe and effective therapies for severe AH. Under the umbrella of these larger aims, the aims of this AlcHepNet proposal are to: Aim 1. Conduct a prospective, multicenter, observational study of patients with AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend our longitudinal database containing 1) clinical and laboratory information and 2) bio-sample repository from subjects with AH of varying severity and matched controls. This database will serve three functions: (a) provide unique information on the outcomes and pathobiology of AH, (b) support translational research designed to identify novel targets for treatment, and (c) serve as a catalyst to develop systems biology-based, informatics- integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform a multicenter, prospective, randomized phase 2B clinical trial of granulocyte colony stimulating factor G- CSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone in patients with severe AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptor antagonist Anakinra (plus zinc) are superior to the standard of care (i.e. Prednisone) in patients with severe AH. The choice of these agents is based on: 1) literature demonstrating a role for inflammation and inflammasome activation in severe AH, 2) several pilot studies demonstrating therapeutic benefit with G-CSF, and 3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. This phase 2B efficacy trial will be conducted across nine clinical centers and coordinated by two Data Coordinating Centers (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet are uniquely positioned to perform the proposed study given the substantial breadth, depth, and history of expertise related to AH, clinical trial conduct, and related therapeutic development. By testing promising therapies for AH and collecting well-annotated patient samples and datasets, this proposal will have a strong and lasting impact on the field.!

摘要