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: 8921359
• 负责人: NAGA P CHALASANI
• 金额: $ 6.68万
• 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/8921359
• 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; Health; 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; 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（由申请方提供）：作为对RFA-AA-12-007的回应，印第安纳州大学（IU）、马约诊所（马约）和弗吉尼亚联邦大学（VCU）已经成立了一个联盟“转化研究和不断发展的酒精性肝炎治疗”（TREAT）。本申请的中心假设是：（a）具有良好表征的急性酒精性肝炎（AH）的患者和匹配对照的大队列极大地增强了我们在人类中进行转化研究以更好地理解其发病机制和开发新治疗的能力，和（B）酒精诱导的经由胆盐受体的信号传导的损伤损害肠道完整性，允许库普弗细胞的活化，增强肝脏中的氧化应激，刺激脂肪肝，并使肝细胞对奎宁诱导的坏死性细胞凋亡敏感，并且这些异常可以用FXR激动剂奥贝胆酸（OCA）逆转。我们将通过以下以患者为导向的研究来解决这些假设。具体目标1：在具有良好特征的AH和适当对照的患者中进行前瞻性多中心观察性研究，作为进行新型机制和治疗研究的基础。将从病例和对照中开发血清/血浆、外周单核细胞、基因组DNA、尿液、粪便样本和肝脏组织（如可用）的稳健中心生物储存库。具体目标二：检验以下假设：酒精诱导的通过法尼醇X受体（FXR，胆盐核受体）的信号传导受损会中断正常的胆盐稳态，并且这将被FXR激动剂奥贝胆酸（OCA）逆转。次要假设是改变的FXR信号传导损害肠道完整性，促进先天免疫应答的激活，增强肝脏氧化应激，并使肝细胞对奎宁诱导的坏死性细胞凋亡敏感。.为了解决这些假设，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。具体目标3：检验FXR激动剂通过纠正其发病机制中涉及的多种异常有效治疗AH的假设。我们将通过在中重度AH患者中开展一项OCA的概念验证、多中心、安慰剂对照、随机对照试验来检验这一假设。60名患有中度AH的成年人将随机接受奥贝胆酸（10 mg，每日一次，口服）或安慰剂治疗4周。主要疗效终点是4周时MELD评分的变化[5]，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联合会另外两名成员提出的另外两项概念验证研究。