Fenofibrate for the treatment of patients with NASH

非诺贝特用于治疗 NASH 患者

• 批准号: 7032512
• 负责人: HARI S CONJEEVARAM
• 金额: $ 15.26万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032512
• 关键词: biopsy; clinical research; clinical trials; clofibrate; fatty acid metabolism; gene expression; hepatitis; histology; human subject; human therapy evaluation; inflammation; insulin sensitivity /resistance; liver; liver disorder chemotherapy; patient oriented research; peroxisome proliferator activated receptor; questionnaires; stimulant /agonist

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)： 非酒精性脂肪性肝炎(NASH)在美国越来越被认为是一种常见的慢性肝病。NASH具有明显的组织学特征，包括脂肪变性、气泡性变性、小叶炎症和不同程度的纤维化。它通常与代谢综合征有关，在美国其发病率正在上升。NASH患者有进展为肝硬变、最终发展为肝细胞癌和过早死亡的风险。目前还没有治疗NASH的标准疗法。在治疗人类和动物NAFLD的小型临床试验中，已经对几种药物治疗方法进行了评估，但由于样本量小、缺乏安慰剂、缺乏后续肝脏活检和/或没有足够的后续随访来评估治疗益处，大多数研究都没有确定的益处。确定肝脏损伤的发病机制、疾病侵袭性形式的预测因素以及精心设计的研究将表明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有效性，这将是这一日益严重的健康问题的主要贡献。我们建议对纤维酸衍生物‘非诺贝特’进行随机、双盲、安慰剂对照研究，非诺贝特是一种PPARa激动剂，在减轻肝脏脂肪变性和炎症方面具有强大的作用，用于治疗组织学证实的NASH患者。我们假设非诺贝特治疗将导致NASH患者脂肪变性和炎症的显着改善，并改善胰岛素敏感性。我们的具体目标是：(1)评估&gt定义的NASH的组织学改善程度；在接受非诺贝特治疗的患者中，使用NASH-CRN评分系统将全球NASH评分降低2分；(2)评估非诺贝特改善NASH患者胰岛素敏感性的效果；(3)评估非诺贝特对NASH患者肝组织PPAR基因表达和脂肪酸代谢的影响。据我们所知，这是第一次在患有NASH的人类中使用PPARa激动剂的随机、安慰剂对照研究。计划中的NASH患者肝组织基因表达分析将首次提供这些药物改变人类肝脏基因表达的作用的快照。我们相信，拟议的研究不仅将有助于我们理解NASH的发病机制，而且将为这种非常重要的疾病的治疗方案提供更多的见解