INTRODUCTION: This study will explore the potential role of silymarin (Sm) in patients with chronic hepatitis C (HCV). The majority of HCV patients are unresponsive to interferon-alfa (IFN?) based therapy. There is some evidence to suggest that Sm may ameliorate liver injury by acting as an antioxidant and by altering lymphocyte responses. These effects could influence HCV by modulating fibrosis and/or viremia.
SPECIFIC AIMS : (1) to determine the safety, tolerability and pharmacokinetics (PK) of a single oral dose administration of Sm relative to placebo in HCV patients non-responsive to IFNa based therapy, (2) to evaluate the therapeutic role of various doses of Sm compared to placebo in HCV patients by assessing parameters of liver injury (alanine aminotransferase [ALT]) ,(3) to evaluate the mechanism of Sm in the above cohort by studying the dose response effect of Sm on oxidative stress (OS) markers, immunological and virological responses, and viral kinetics and (4) to define rational dosing criteria constructed from exposure-response relationships based on PK and Pharmodynamic (PD) modeling. METHODS: (i) Part one of this double-blind, placebo-controlled study of safety, and PK/PD parameters in Sm in HCV patients non-responsive to IFN? will assess single dose Sm in an alternating panel, rising dose design, with >7 days between treatments (ii) Based on (i), multiple dose administration of Sm over 4 weeks will be assessed with regard to PK, OS and T-cell function, with the aim of selecting doses for phase II studies in this population, (iii) Two optimal doses based on (ii) will be administered over 48 weeks evaluating ALT response and the above parameters. Primary outcome will be ALT response (decline >50% or to <60 ILJ/mL). Sm and its individual components will be measued by LC/MS/MS, OS by LC/MS/MS quantitation of urinary isoprostanes, immune responsiveness by HCV-specific and phytohemagglutinin-mediated CD4 T cell responses, and viral titers by quantitative reverse transcriptase PCR. Based on a sample size of 160, this study will have a 80% power to detect a 14% difference of response at an alpha error of 0.05. LAY SUMMARY: Many patients take milk thistle for hepatitis C, but we do not know if it is of any help or harm. This study will examine the safety and tolerability of various doses of milk thistle as well as start to explore its role in hepatitis C.
