Alcoholic Hepatitis Clinical and Translational Network - Late Phase Clinical Trials and Observational Studies (Collaborative U01)

酒精性肝炎临床和转化网络 - 后期临床试验和观察研究（合作 U01）

• 批准号: 9764890
• 负责人: Srinivasan Dasarathy
• 金额: $ 0.84万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764890
• 关键词: Alcoholic Hepatitis; CSF3 gene; Clinic; Clinical; Clinical Trials; Conduct Clinical Trials; Data Coordinating Center; Data Set; Databases; FDA approved; Foundations; Funding; Goals; Granulocyte Colony-Stimulating Factor; Hepatitis B; Inflammasome; Inflammation; Informatics; Institution; 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; Treatment Efficacy; Zinc; active method; anakinra; base; catalyst; effective therapy; efficacy trial; interest; longitudinal database; mortality; new therapeutic target; novel; primary endpoint; prospective; repository; standard of care; therapeutic development; treatment arm; Alcoholic Hepatitis; CSF3 gene; Clinic; Clinical; Clinical Trials; Conduct Clinical Trials; Data Coordinating Center; Data Set; Databases; FDA approved; Foundations; Funding; Goals; Granulocyte Colony-Stimulating Factor; Hepatitis B; Inflammasome; Inflammation; Informatics; Institution; 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; Treatment Efficacy; Zinc; active method; anakinra; base; catalyst; effective therapy; efficacy trial; interest; longitudinal database; mortality; new therapeutic target; novel; primary endpoint; prospective; repository; standard of care; therapeutic development; treatment arm

Institution: Cleveland Clinic PI: Srinivasan Dasarathy ABSTRACT of the original application: 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 GCSF 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.

机构：克利夫兰诊所 PI：Srinivasan Dasarathy 原始应用程序的摘要： 酒精性肝炎（AH）是与肝有关的发病率和死亡率的主要原因，显着匮乏 有效的治疗学。该申请代表了几个NIAAA资助的财团的协调提交 作为酒精性肝炎网络（Alchepnet），它们都聚集在一起。集体网络将协同作用 努力和专业知识，以更好地理解AH并为严重AH开发新颖的有效和安全疗法。 为了支撑这个目标，这个新财团的总体目的是：1）进行研究以更好地理解 结局的发病机理和主要决定因素，特别是在严重的AH中； 2）确定新的目标 AH的疗法和3）对已经批准的FDA进行的2B期研究，可用 并可以重新使用为严重AH的安全有效疗法。在这些较大目标的保护下， 该炼金术提案的目的是：目标1。进行一项前瞻性，多中心，观察性研究 具有AH的患者和合适的对照，这是进行新机械和的基础 治疗研究。我们将合并并扩展包含1）临床和的纵向数据库 实验室信息和2）来自AH的受试者的生物样本存储库，并且匹配不同 控件。该数据库将提供三个功能：（a）提供有关结果和的独特信息 AH的病理生物学，（b）支持旨在识别治疗新目标的转化研究，（c） 作为开发基于系统生物学的，信息学集成数据库的催化剂，该数据库将作为一个 所有对AH感兴趣的研究人员的资源； AIM 2。执行多中心，前瞻性，随机阶段2b 粒细胞菌落刺激因子GCSF与Anakinra（加锌）与标准医学的临床试验 严重AH患者的泼尼松治疗。这个目的将检验两个主动治疗的假设 具有G-CSF和IL-1受体拮抗剂Anakinra（加锌）的手臂优于护理标准（即 严重AH患者的泼尼松）。这些代理的选择基于：1）文学证明了 在严重AH中炎症和炎症体激活的作用，2）几项初步研究证明 G-CSF的治疗益处和3）正在进行的试验的临时分析表明，死亡率益处 Anakinra AH患者。该2B期疗效试验将在9个临床中心进行， 由两个数据协调中心（DCC）协调。主要终点将是第90天的死亡率。 研究人员和炼金术人员的独特位置可以进行拟议的研究，鉴于大量的研究 与AH，临床试验行为以及相关治疗发展有关的专业知识的广度，深度和历史。 通过测试AH的有希望的疗法并收集良好的患者样品和数据集，该建议 将对该领域产生强烈而持久的影响。