Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 9/9

酒精性肝炎临床和转化网络后期临床试验和观察研究 9/9

基本信息

批准号：
9752430
负责人：
ARUN J SANYAL
金额：
$ 36.34万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752430
关键词：
Adrenal Cortex Hormones Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Caring Clinical Clinical Research Clinical Trials Clinical Trials Design Collection Conduct Clinical Trials Consumption Data Coordinating Center Data Set Databases Development Disease Economic Burden Educational workshop Eligibility Determination Foundations Funding Future Goals Grant Granulocyte Colony-Stimulating Factor Infection Inflammasome Inflammation Informatics Interleukin-1 Receptors Interleukin-1 beta Label Laboratories Learning Life 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 Research Design Research Personnel Resources Role Sampling Severities Systems Biology Testing Therapeutic Therapeutic Studies Translational Research Treatment Efficacy Validation Work Zinc active method anakinra base drug testing effective therapy efficacy trial evidence base improved insight interest liver injury longitudinal database meetings mortality new therapeutic target novel prednisolone primary endpoint problem drinker prospective receptor repository research study secondary endpoint standard of care targeted treatment therapeutic development translational study treatment arm

项目摘要

Abstract Alcoholic (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 which have come together as the Alcoholic Hepatitis Network (AlcHepNet) to better understand AH and develop novel effective and safe therapy for severe AH. The overarching aims of this consortium are to: (1) perform studies to better understand the pathogenesis and main determinants of outcome, particularly in severe AH, (2) identify novel targets for therapy of AH, and (3) perform phase 2B studies of compounds that are already available and can be repurposed as safe and effective therapy for severe AH. Under the umbrella of these larger aims, the aims of this proposal are: 1. To 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 of (1) clinical and laboratory information and (2) a bio-sample repository from subjects with AH of varying severity and matched-controls. This database will: (a) provide unique information on the outcomes and pathobiology of AH, (b) support translational research designed to identify novel targets for treatment, and (c) be used to generate systems biology based informatics-integrated databases that will serve as a resource for all researchers interested in AH. 2. To perform a multicenter prospective, randomized phase 2B clinical trial of G-CSF and Anakinra versus standard medical therapy with Prednisolone 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 are superior to the stardard of care (i.e. prednisolone) 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, (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 a Data Coordinating Center (DCC). The primary endpoint will be mortality at day 90. The investigators and the AlcHepNet is uniquely positioned to perform the proposed study given substantial breadth and depth of expertise related to AH, clinical trial conduct, and therapeutic development. By testing promising therapies for AH and concurrently collecting well annotated patient samples and datasets, this proposal will have a strong and lasting impact on the field.

抽象的酒精（AH）是肝脏相关发病率和死亡率的主要原因，具有显着的影响缺乏有效的治疗方法。该申请代表协调提交几个由 NIAAA 资助的财团联合起来组成了酒精性肝炎网络 (AlcHepNet) 更好地了解 AH 并开发新的有效且安全的重症治疗方法啊。该联盟的总体目标是：(1) 进行研究以更好地了解发病机制和结果的主要决定因素，特别是在严重的 AH 中，(2) 确定 AH 治疗的新靶标，以及 (3) 对以下化合物进行 2B 期研究：已经可用，并且可以重新用作严重 AH 的安全有效的治疗方法。下综合这些更大的目标，本提案的目标是： 1. 开展前瞻性、对 AH 患者和合适对照进行的多中心观察性研究，作为进行新颖的机制和治疗研究的基础。我们将巩固和扩展我们的纵向数据库 (1) 临床和实验室信息以及 (2) 来自不同严重程度的 AH 受试者和匹配对照的生物样本库。该数据库将：(a) 提供有关 AH 结果和病理学的独特信息，(b) 支持旨在确定新治疗靶点的转化研究，并且 (c) 被使用生成基于系统生物学的信息学集成数据库，该数据库将作为为所有对 AH 感兴趣的研究人员提供的资源。 2. 为了进行多中心前瞻性， G-CSF 和 Anakinra 与标准医疗的随机 2B 期临床试验严重 AH 患者使用泼尼松龙治疗。这个目标将检验以下假设： G-CSF 和 IL-1 受体拮抗剂 Anakinra 的两个积极治疗组均优于严重 AH 患者的护理标准（即泼尼松龙）。这些代理的选择基于：（1）文献证明炎症和炎性体激活在严重 AH，(2) 多项初步研究证明 G-CSF 具有治疗功效，(3) 中期研究对一项正在进行的试验的分析表明阿那白滞素可以降低 AH 患者的死亡率。这项 2B 期疗效试验将在九个临床中心进行，并由数据协调中心（DCC）。主要终点是第 90 天的死亡率。研究人员和 AlcHepNet 具有独特的优势来执行拟议的研究与 AH、临床试验实施和治疗相关的专业知识的广度和深度发展。通过测试有前景的 AH 疗法并同时收集注释良好的信息患者样本和数据集，该提案将对该领域产生强烈而持久的影响。