Silymarin for the Treatment of Nonalcoholic Steatohepatitis

描述（由申请人提供）：非酒精性脂肪性肝炎（NASH）是肝脏相关疾病的重要原因。鉴于肥胖和2型糖尿病患者处于危险之中，而且这些过程在美国很常见，旨在寻找治疗方法的研究的影响是深远的。由于其抗氧化特性，水飞蓟素可能作为一种有效的治疗NASH的药物，这一过程与氧化损伤有关。因此，本研究的主要目的是确定水飞蓟素在伴有两种最常见相关疾病（肥胖和2型糖尿病）的NASH患者中的安全性、耐受性和有效性。I期研究的第一部分是一项剂量发现研究，采用递增剂量的顺序，交替治疗肥胖NASH患者组。本研究旨在评估水飞蓟素最大耐受剂量下水飞蓟素在稳态条件下的安全性、耐受性和药代动力学特征。本研究的主要终点是不良事件的发生率和AUC（0-12hr）的药代动力学参数。I期的第二部分将评估水飞蓟素在2型糖尿病合并NASH患者中的安全性和耐受性，由于口服降糖药的潜在相互作用，该研究与肥胖患者分开研究。具体来说，我们将比较肥胖NASH患者与口服分泌剂（磺脲类、瑞格列奈、那格列奈、格列脲）联合或不联合胰岛素治疗的2型糖尿病NASH患者的AUC（0-12hr）药代动力学参数和不良事件发生率。该II期研究将包括为期48周的安慰剂对照双盲随机试验，水飞蓟素用于NASH合并肥胖或2型糖尿病患者。主要终点是与基线相比，水飞蓟素组与安慰剂组患者肝脏组织学的改善。

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is an important cause of liver related morbidity. Given that obese and type 2 diabetic patients are at risk and these processes are common in the U.S., the impact of research aimed at finding a therapy is far reaching. By virtue of its antioxidant properties, Silymarin may have a plausible role as an effective therapy for NASH, a process in which oxidant injury has been implicated. Therefore, the broad aims of this research are to establish the safety, tolerability, and efficacy of Silymarin in NASH patients with two of the most commonly associated disorders, obesity and type 2 diabetes. The first part of the Phase I study is a dose-finding study using a sequence of escalating doses with alternating groups of obese patients with NASH. This study design aims to assess the safety, tolerability, and pharmacokinetic profile of silibinin at steady state conditions at a maximally tolerated dose of Silymarin. The primary endpoints of this study will be the incidence of adverse events and the pharmacokinetic parameter of AUC(0-12hr). The second part of phase I will assess the safety and tolerability of Silymarin in type 2 diabetics with NASH, studied separately from the obese patients due to the potential interacting effect of oral hypoglycemics. Specifically, we will compare the pharmacokinetic parameter of AUC(0-12hr) and the incidence of adverse events in obese patients with NASH to type 2 diabetics with NASH who are treated with oral secretagogues (sulfonylureas, repaglinide, nateglinide, glimepiride) with or without insulin. The phase II study will comprise a 48 week placebo controlled double blind randomized trial of Silymarin in patients with NASH and obesity or type 2 diabetes. The primary endpoint will be the improvement in hepatic histology, compared to baseline, in Silymarin versus placebo treated patients. Relevance to Public Health: This research addresses an increasingly common problem in a large segment of the U.S. population; that is, liver injury caused by fat in obese and diabetic patients. Silymarin has been used for many centuries for the treatment of liver diseases and has been shown to be safe. This research will prove the safety and effectiveness of Silymarin for liver injury caused by fat in obese and diabetic patients, in carefully designed scientific trials. These results will allow practitioners and patients to decide whether to use Silymarin in this specific disease process.