Fenofibrate for the treatment of patients with NASH

非诺贝特用于治疗 NASH 患者

• 批准号: 7178464
• 负责人: HARI S CONJEEVARAM
• 金额: $ 14.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178464
• 关键词: Acids; Agonist; Alcohols; Animals; Cessation of life; Chronic; Cirrhosis; Clinical; Clinical Treatment; Clinical Trials; Condition; Disease; Disease Progression; Double-Blind Method; Drug effect disorder; Economics; Fatty Liver; Fenofibrate; Fibrosis; Gene Expression; Hepatic; Histologic; Human; Incidence; Individual; Inflammation; Injury; Insulin Resistance; Intervention; Knowledge; Lead; Lipid Peroxidation; Liver; Liver Failure; Liver diseases; Lobular; Medical; Metabolic syndrome; Numbers; Pathogenesis; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacotherapy; Placebos; Prevalence; Primary carcinoma of the liver cells; Randomized; Range; Receptor Gene; Research Design; Risk; Sample Size; Score; Severities; Standards of Weights and Measures; Steatohepatitis; System; Testing; Time; Tissues; United States; fatty acid metabolism; follow-up; improved; insight; insulin sensitivity; liver biopsy; non-alcoholic fatty liver; nonalcoholic steatohepatitis; outcome forecast; placebo controlled study; randomized placebo controlled trial

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is increasingly recognized as a common form of chronic liver disease in the United States. NASH is characterized by distinct histological features that include steatosis, ballooning degeneration, lobular inflammation and varying degrees of fibrosis. It is commonly associated with the metabolic syndrome, the incidence of which is rising in the U.S. Patients with NASH are at risk of progression to cirrhosis and ultimately to hepatocellular carcinoma and premature death. There is no standard therapy for management of NASH at this point. Several approaches to drug therapy have been evaluated in small clinical trials for the treatment of NAFLD in humans and in animals but most studies have been inconclusive with uncertain benefits because of small sample size, lack of placebo, lack of follow-up liver biopsies and/or inadequate follow-up to evaluate treatment benefit. Studies that identify the pathogenesis of liver injury, predictors of aggressive forms of the disease as well as well designed studies that will show efficacy of medical interventions aimed at improving steatosis and inflammation and slowing down progression of disease will be major contributions for this growing health-problem. We propose a randomized, double-blind, placebo controlled study of a fibric acid derivative 'fenofibrate', a PPARa agonist with potent effects in decreasing hepatic steatosis and inflammation for treatment of patients with histologically proven NASH. We hypothesize that fenofibrate treatment will lead to a significant improvement in steatosis and inflammation and improve insulin sensitivity in patients with NASH. Our specific aims are: (1) To assess the degree of histological improvement of NASH as defined by > 2 point decrease in global NASH score using the NASH-CRN scoring system in patients undergoing treatment with fenofibrate, (2) To assess the effect of fenofibrate in improving insulin sensitivity in patients with NASH and (3) To assess the effect of fenofibrate on PPAR gene expression and fatty acid metabolism in liver tissue of patients with NASH. To our knowledge, this is the first randomized, placebo-controlled study of a PPARa agonist in humans with NASH. The planned gene expression analysis in liver tissue of patients with NASH will provide, for the first time, a snapshot of the action of these drugs to change hepatic gene expression in humans. We believe that the proposed studies will be an important contribution to our understanding not only of the pathogenesis of NASH, but will provide additional insights into treatment options for this very important disease

描述（由申请人提供）： 在美国，非酒精性脂肪性肝炎 (NASH) 越来越被认为是一种常见的慢性肝病。 NASH 具有独特的组织学特征，包括脂肪变性、气球样变性、小叶炎症和不同程度的纤维化。它通常与代谢综合征相关，在美国，代谢综合征的发病率正在上升。 NASH 患者有发展为肝硬化、最终发展为肝细胞癌和过早死亡的风险。目前尚无治疗 NASH 的标准疗法。已经在小型临床试验中评估了几种治疗人类和动物 NAFLD 的药物治疗方法，但由于样本量小、缺乏安慰剂、缺乏后续肝活检和/或评估治疗效果的随访不充分，大多数研究都没有得出结论，其疗效不确定。确定肝损伤发病机制的研究、该疾病侵袭性形式的预测因素以及精心设计的研究将显示旨在改善脂肪变性和炎症并减缓疾病进展的医疗干预措施的功效，这将是解决这一日益严重的健康问题的主要贡献。我们提出了一项针对纤维酸衍生物“非诺贝特”的随机、双盲、安慰剂对照研究，这种药物是一种 PPARa 激动剂，具有有效减少肝脏脂肪变性和炎症的作用，可用于治疗经组织学证实的 NASH 患者。我们假设非诺贝特治疗将显着改善脂肪变性和炎症，并提高 NASH 患者的胰岛素敏感性。我们的具体目标是：(1) 评估接受非诺贝特治疗的患者中 NASH 组织学改善程度，定义为使用 NASH-CRN 评分系统使总体 NASH 评分降低 > 2 分，(2) 评估非诺贝特在改善 NASH 患者胰岛素敏感性方面的作用，(3) 评估非诺贝特对非诺贝特肝组织中 PPAR 基因表达和脂肪酸代谢的影响 NASH 患者。据我们所知，这是第一个针对 NASH 患者 PPARa 激动剂的随机、安慰剂对照研究。计划对 NASH 患者肝组织进行基因表达分析，这将首次提供这些药物改变人类肝基因表达作用的概况。我们相信，拟议的研究不仅将为我们理解 NASH 的发病机制做出重要贡献，还将为这种非常重要的疾病的治疗方案提供更多见解