ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES6/9

酒精性肝炎临床和转化网络：后期临床试验和观察研究6/9

• 批准号: 10876683
• 负责人: Srinivasan Dasarathy
• 金额: $ 10万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/10876683
• 关键词: Alcoholic Hepatitis; Biological Specimen Banks; CSF3 gene; Clinical; Clinical Trials; Conduct Clinical Trials; Data Coordinating Center; Data Set; Databases; FDA approved; Foundations; Funding; Goals; Granulocyte Colony-Stimulating Factor; Inflammasome; Inflammation; Informatics; Interleukin-1 Receptors; Laboratories; Literature; Liver; Medical; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Observational Study; Outcome; Pathogenesis; Patients; Phase; Pilot Projects; Positioning Attribute; Prednisone; Randomized; Recording of previous events; Research Design; Research Personnel; Resources; Role; Sampling; Severities; Systems Biology; Testing; Therapeutic; Therapeutic Studies; Translational Research; Zinc; active method; anakinra; antagonist; catalyst; clinical center; effective therapy; efficacy trial; interest; longitudinal database; mortality; new therapeutic target; novel; primary endpoint; prospective; standard of care; synergism; therapeutic development; therapeutically effective; treatment arm

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 酒精性肝炎（AH）是肝脏相关发病率和死亡率的主要原因， 有效的治疗方法。此应用程序代表了几个NIAAA资助的协调提交 酒精性肝炎网络（AlcHepNet）。总的来说，网络 将协同努力和专业知识，以更好地了解AH，并开发新的有效和安全的治疗方法， 严重啊。为了支持这一目标，这个新的联合体的总体目标是：1）进行研究， 更好地了解发病机制和结局的主要决定因素，特别是在重度AH中; 2）识别 AH治疗的新靶点，以及3）对已经FDA批准的化合物进行2B期研究 已获批准并可用，可重新用作重度AH的安全有效疗法。下 在这些更大目标的保护伞下，AlcHepNet提案的目标是：目标1。进行前瞻性， AH患者和适当对照的多中心、观察性研究， 进行新的机制和治疗研究的基础。我们将巩固和扩大我们的 纵向数据库，包含1）临床和实验室信息和2）生物样本储存库， 严重程度不同的AH受试者和匹配对照。该数据库将发挥三项职能： 关于AH的结局和病理生物学的独特信息，（B）支持旨在 确定新治疗目标，以及（c）作为开发基于生物学、信息学的系统的催化剂， 综合数据库，将作为所有对AH感兴趣的研究人员的资源;目标2。执行 粒细胞集落刺激因子G的多中心、前瞻性、随机化2B期临床试验- CSF与阿那白滞素（加锌）与泼尼松标准药物治疗对 严重啊。这一目的将检验以下假设，即G-CSF和IL-1受体的两个活性治疗组 拮抗剂阿那白滞素（加锌）在重度糖尿病患者中的疗效上级于标准治疗（即泼尼松）。 啊这些药物的选择基于：1）文献证明了炎症的作用， 严重AH中的炎性小体活化，2）几项初步研究证实了G-CSF的治疗益处， 和3）正在进行的试验的中期分析表明阿那白滞素对AH患者的死亡率有益。这 2B期疗效试验将在9个临床中心进行，并由两个数据协调中心协调 中心（DCCs）。主要终点为第90天的死亡率。调查人员和AlcHepNet正在 独特的定位，以执行拟议的研究，鉴于实质性的广度，深度和历史， 与AH、临床试验实施和相关治疗开发相关的专业知识。通过测试， 治疗AH和收集注释良好的患者样本和数据集，这项建议将有很强的 并对该领域产生持久的影响。