A phase I/II randomized, placebo controlled trial of silymarin for hepatitis C

描述（由申请人提供）：在过去十年中，在慢性丙型肝炎的抗病毒治疗领域取得了重大进展。大约50%的患者联合使用聚乙二醇干扰素和利巴韦林治疗后获得了持续的病毒学应答。不幸的是，其余的患者要么没有反应，要么由于不良事件而必须提前停止治疗。此外，大量慢性丙型肝炎患者从未接受过治疗，因为他们对目前可用药物的严格治疗有禁忌症。需要额外的治疗选择。几个世纪以来，草药产品一直被经验性地用作治疗各种人类疾病的替代药物。水飞蓟，或水飞蓟素，主要用于其声称的有益效果在肝脏疾病，其中包括抗炎，抗氧化和抗纤维化活性。然而，临床试验几乎没有证据支持使用水飞蓟素作为肝脏疾病的治疗。先前关于水飞蓟素的肝保护作用的临床研究的几个主要局限性包括：1）使用非标准化的水飞蓟素提取物2）对水飞蓟素剂量与水飞蓟素的潜在活性异构体的稳态暴露之间的关系的不完全理解，混淆了安全性和功效的评价;和3）使用异质性患者群体和可变终点来评估治疗反应。在本申请中，我们将集中在设计的I期药代动力学研究，将高水飞蓟素剂量和受试者暴露于四个异构体的水飞蓟素之间的关系的特点。从I期研究中获得的信息将允许合理决定用于II期研究的剂量，然后进行II期研究，以评估水飞蓟素治疗既往接受常规治疗的慢性丙型肝炎受试者的安全性和有效性。我们作为临床中心参与这项合作研究的申请将强调肝脏项目和查佩尔山的北卡罗来纳州大学药学院的独特属性和药物开发专业知识，这将确保成功完成这项合作项目。

DESCRIPTION (provided by applicant): Major advances have been made over the last decade in the field of antiviral therapy for chronic hepatitis C. Approximately 50% of patients treated with the combination of peginterferon and ribavirin achieve a sustained virological response. Unfortunately, the remainder either fails to respond or must discontinue treatment prematurely due to adverse events. In addition, a significant number of patients with chronic hepatitis C are never offered therapy because they have contraindications to the rigors of treatment with currently available medications. Additional therapeutic options are needed. Herbal products have been used empirically for centuries as alternative medicines to treat a variety of human disorders. Silybum marianum, or silymarin, is primarily used for its purported beneficial effects in disorders of the liver, which include anti-inflammatory, anti-oxidant, and anti-fibrogenic activities. However, there is little evidence from clinical trials to support the use of silymarin as a treatment for diseases of the liver. Several major limitations of prior clinical investigations on the hepatoprotective effects of silymarin include: 1) the use of non- standardized silymarin extracts 2) the incomplete understanding of the relationship between silymarin dose and steady-state exposures to the potentially active isomers of silymarin, confounding the evaluation of safety and efficacy; and 3) the use of heterogeneous patient populations and variable endpoints to assess therapeutic response. In this application we will focus on the design of a phase I pharmacokinetic study that will characterize relationships between high silymarin doses and subject exposure to the four isomers of silymarin. The information obtained from the phase I study will allow a rational decision regarding dosages to be used for a phase II study that will then be performed to evaluate the safety and efficacy of silymarin for the treatment on subjects with chronic hepatitis C who were previously treated with conventional therapies. Our application to participate as a Clinical Center for this cooperative study will emphasize the unique attributes and expertise in drug development of the Liver Program and the faculty at the School of Pharmacy at the University of North Carolina at Chapel Hill that will ensure successful completion of this collaborative project.