Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 4/9

酒精性肝炎临床和转化网络后期临床试验和观察研究 4/9

• 批准号: 10202390
• 负责人: Gyongyi Szabo
• 金额: $ 34.99万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202390
• 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; Validation; Work; Zinc; active method; anakinra; base; catalyst; clinical center; drug testing; effective therapy; efficacy trial; 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

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.!

抽象的 酒精性肝炎 (AH) 是肝脏相关发病率和死亡率的主要原因，但其发病率却非常低 有效的治疗方法。该申请代表了多个 NIAAA 资助的机构的协调提交 联盟组成了酒精性肝炎网络 (AlcHepNet)。总的来说，网络 将协同努力和专业知识，更好地了解 AH 并开发新的有效且安全的疗法 严重啊。为了支持这一目标，这个新联盟的总体目标是：1）进行研究 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）识别 AH 治疗的新靶标，以及 3) 对已获得 FDA 批准的化合物进行 2B 期研究 已获得批准并可用，并且可以重新用作严重 AH 的安全有效的治疗方法。下 在这些更大的目标中，AlcHepNet 提案的目标是： 目标 1. 进行前瞻性、 对 AH 患者和合适对照进行的多中心观察性研究 为进行新的机制和治疗研究奠定了基础。我们将巩固和拓展我们的 纵向数据库包含 1) 临床和实验室信息以及 2) 生物样本库 患有不同严重程度的 AH 的受试者和匹配的对照。该数据库将提供三个功能：(a) 提供 关于 AH 的结果和病理学的独特信息，(b) 支持旨在 确定新的治疗目标，以及（c）作为开发基于生物学、信息学的系统的催化剂 综合数据库将成为所有对 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2B期临床试验 CSF 对比阿那白滞素（加锌）对比泼尼松标准药物治疗 严重啊。该目标将检验以下假设：G-CSF 和 IL-1 受体的主动治疗组 对于重症患者，拮抗剂阿那白滞素（加锌）优于标准治疗（即泼尼松） 啊。这些药物的选择基于：1) 文献证明其对炎症和炎症的作用 严重 AH 中的炎症小体激活，2) 多项初步研究证明 G-CSF 具有治疗功效， 3) 一项正在进行的试验的中期分析表明阿那白滞素可以降低 AH 患者的死亡率。这 2B 期疗效试验将在九个临床中心进行，并由两个数据协调中心协调 中心（DCC）。主要终点是第 90 天的死亡率。研究人员和 AlcHepNet 鉴于该研究的广度、深度和历史，具有独特的优势来执行拟议的研究 与 AH、临床试验实施和相关治疗开发相关的专业知识。通过测试有希望 治疗 AH 并收集注释良好的患者样本和数据集，该提案将具有强大的影响力 并在该领域产生持久的影响。