Translational Research and Evolving Alcoholic hepatitis Treatment (TREAT-IU)

转化研究和不断发展的酒精性肝炎治疗 (TREAT-IU)

• 批准号: 8695260
• 负责人: NAGA P CHALASANI
• 金额: $ 100.62万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695260
• 关键词: Acids; Acute Alcoholic Hepatitis; Address; Adrenal Cortex Hormones; Adult; Affect; Age; Agonist; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Antibodies; Back; Bacterial Translocation; Bile Acids; CYP2E1 gene; Caspase Inhibitor; Cells; Clinic; Clinical; Drug Kinetics; Enrollment; Fatty Liver; Feces; Fibroblast Growth Factor; Foundations; Functional disorder; Gender; Genomic DNA; Glossary; Goals; Heavy Drinking; Hepatic; Hepatocyte; Histologic; Homeostasis; Hospitalization; Human; Immune response; Impairment; Incidence; Indiana; Individual; Inflammation; Injury to Liver; Kupffer Cells; Laboratories; Length of Stay; Lipopolysaccharides; Liver; Liver diseases; Metabolism; Modeling; Mononuclear; Morbidity - disease rate; Multiple Abnormalities; Natural Immunity; Nuclear Receptors; Observational Study; Oral; Oral cavity; Oxidative Stress; Pathogenesis; Pathway interactions; Patient Care; Patients; Peripheral; Permeability; Placebo Control; Placebos; Plasma; Public Health; Questionnaires; Race; Randomized; Randomized Controlled Trials; Recording of previous events; Research Personnel; Safety; Sample Size; Sampling; Serious Adverse Event; Severities; Signal Transduction; Staging; Testing; Therapeutic Studies; Time; Tissues; Translational Research; Universities; Urine; Virginia; alcohol research; bile salts; case control; cohort; cytokine; drinking; effective therapy; meetings; member; mortality; named group; novel; novel strategies; patient oriented research; prospective; public health relevance; receptor; repository; response; therapy development; translational study

DESCRIPTION (provided by applicant): In response to the RFA-AA-12-007, Indiana University (IU), Mayo Clinic (Mayo), and Virginia Commonwealth University (VCU) have formed a consortium "Translational Research and Evolving Alcoholic Hepatitis Treatments"(TREAT). Central hypotheses of this application are: (a) a large cohort of patients with well-characterized acute alcoholic hepatitis (AH) and matched controls greatly enhances our ability to conduct translational studies in humans to better understand its pathogenesis and to develop novel treatments, and (b) alcohol-induced impairment of signaling via bile salt receptors impairs gut integrity, permits activation of Kupffer cells, enhances oxidative stress in the liver, stimulates fatty liver, and sensitizes hepatocytes to cytokine-induced necroapoptosis, and that these abnormalities can be reversed with the FXR agonist, obeticholic acid (OCA). We will address these hypotheses by conducting the following patient- oriented studies. Specific Aim 1: To conduct a prospective multicenter observational study of patients with well-characterized AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. A robust central bio-repository of serum/plasma, peripheral mononuclear cells, genomic DNA, urine, stool samples, and liver tissue (where available) will be developed from both cases and controls. Specific Aim 2: To test the hypothesis that alcohol-induced impairment of signaling via farnesoid X receptor (FXR, the bile salt nuclear receptor) interrupts normal bile salt homeostasis, and that this will be reversed with an FXR agonist, obeticholic acids (OCA). A secondary hypothesis is that altered FXR signaling impairs gut integrity, promotes activation of the innate immune response, enhances hepatic oxidative stress, and sensitizes hepatocytes to cytokine-induced necroapoptosis. . To address these hypotheses, we will conduct a study of bile salt metabolism and effects of OCA in heavy drinkers without liver disease (n=15), moderate drinkers (n=15), and non-drinkers (n=15). Specific Aim 3: To test the hypothesis that FXR agonists are effective in treating AH by correcting multiple abnormalities implicated in its pathogenesis. We will test this hypothesis by conducting a proof-of-concept multicenter, placebo-controlled randomized controlled trial of OCA in patients with moderately severe AH. Sixty adults with AH of moderate severity will be randomized to receive either obeticholic acid (10 mg once daily by mouth) or placebo for 4 weeks. Primary efficacy end point is change in MELD score at 4 weeks [5] and the primary safety end point is the incidence of serious adverse events (SAE) at 4 weeks. Specific aim 4: To participate in the two other proof-of-concept studies proposed by the other two members of the TREAT consortium.

描述（由申请人提供）：根据RFA-AA-12-007，印第安纳大学（IU）、梅奥诊所（Mayo）和弗吉尼亚联邦大学（VCU）组成了一个“转化研究和不断发展的酒精性肝炎治疗”（TREAT）联盟。本应用的中心假设是：(a)一大批具有明确特征的急性酒精性肝炎（AH）患者和匹配的对照组极大地增强了我们在人类中进行转化研究的能力，以更好地了解其发病机制并开发新的治疗方法；(b)酒精诱导的通过胆盐受体的信号损伤损害了肠道完整性，允许库普弗细胞的激活，增强了肝脏中的氧化应激，刺激了脂肪肝。并使肝细胞对细胞因子诱导的坏死细胞凋亡敏感，这些异常可以通过FXR激动剂奥贝胆酸（OCA）逆转。我们将通过以下以病人为导向的研究来解决这些假设。具体目标1：开展一项前瞻性多中心观察性研究，纳入特征明确的AH患者和合适的对照，为开展新的机制和治疗研究奠定基础。将从病例和对照中建立一个强大的中央生物库，包括血清/血浆、外周单核细胞、基因组DNA、尿液、粪便样本和肝组织（如有）。特定目的2：验证酒精诱导的通过法内甾体X受体（FXR，胆盐核受体）的信号通路损伤会中断正常的胆盐稳态，而FXR激动剂奥比胆酸（OCA）会逆转这一假设。另一种假设是，FXR信号的改变会损害肠道完整性，促进先天免疫反应的激活，增强肝脏氧化应激，并使肝细胞对细胞因子诱导的坏死细胞凋亡敏感。为了验证这些假设，我们将在无肝病的重度饮酒者（n=15）、中度饮酒者（n=15）和非饮酒者（n=15）中进行胆盐代谢和OCA影响的研究。特异性目的3：验证FXR激动剂通过纠正与AH发病机制相关的多种异常而有效治疗AH的假设。我们将通过对中重度AH患者进行OCA的多中心、安慰剂对照随机对照试验来验证这一假设。60名中度AH成人患者将随机接受奥比胆酸（10mg，每日一次，口服）或安慰剂治疗，为期4周。主要疗效终点是4周时MELD评分的变化，主要安全性终点是4周时严重不良事件（SAE）的发生率。具体目标4：参与TREAT联盟其他两名成员提出的另外两项概念验证研究。