The Silymarin Trial for Hepatitis C and NASH (SyNCH) is a randomized, double-masked, placebo-controlled phase II study that assessed the safety and efficacy of a standardized orally administered silymarin preparation (Legalon®) for the treatment of patients with chronic hepatitis C virus (HCV) who failed conventional antiviral therapy. The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. In light of inconclusive past clinical trials, the SyNCH study aimed to determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV). In the phase I trial, an initial dose-ranging study was performed to identify silymarin doses for further study. Two doses, 3 and 5 times higher than the customary dose, were selected for the phase II trial based on this early testing.

The study enrolled participants with chronic HCV infection and serum alanine aminotransferase (ALT) levels of at least 65 U/L who were previously unsuccessfully treated with interferon-based therapy were enrolled. Participants were randomly assigned to 1 of 3 groups: 420-mg silymarin, 700-mg silymarin, or matching placebo gelatin capsules administered 3 times daily for 24 weeks, a standard duration of treatment for which effective therapies for HCV have regularly demonstrated improvement in disease activity. The primary outcome measure for efficacy was serum ALT level of 45 U/L or less (approximate normal range) or attainment of at least 50% decline of ALT level to less than 65 U/L after the 24-week treatment period. Results showed that after 24 weeks of treatment, only 2 participants in each treatment group met the primary outcome measure: 3.8% for placebo, 4.0% for 420-mg silymarin, and 3.8% for 700-mg silymarin. Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.

The primary objective of the study was to determine the effect of silymarin on liver disease activity in patients with chronic HCV infection who had been unsuccessfully treated with interferon-based therapy. Secondary objectives included characterizing the effect of silymarin on serum levels of HCV RNA and exploring relationships between silymarin therapy and serum biomarkers of HCV hepatic disease activity, such as oxidative stress, apoptosis, and fibrogenesis.

The primary outcome measure for efficacy was serum ALT level of 45 U/L or less (approximate normal range) or attainment of at least 50% decline of serum ALT level to less than 65 U/L (approximately 1.5 times the upper limit of normal) after the 24-week treatment period. The change in serum ALT level was chosen as the primary outcome in this study as it has been correlated with improvement in hepatic necroinflammatory activity during studies of interferon for HCV infection.

Secondary outcomes measures included change in serum ALT and serum HCV RNA levels during treatment. Adverse events were also monitored.

Patients ages 18 years and older with chronic HCV infection were eligible for the trial if they had:

• Received previous IFN-based therapy without sustained virological response
• Quantifiable serum HCV RNA levels
• An alanine aminotransferase (ALT) level of 65 U/L or greater at screening.

Patients were excluded from the study if they had:

• Evidence of decompensated hepatic cirrhosis
• A positive HIV antibody test result or positive result for HBsAg (surface antigen of the hepatitis B virus)
• Used milk thistle products within the previous 30 days

Results showed that only 2 participants in each treatment group met the primary outcome measure: 3.8% for placebo, 4.0% for 420-mg silymarin, and 3.8% for 700-mg silymarin, after 24 weeks of treatment. There was no statistically significant difference across treatment groups when changes in serum ALT levels from baseline to end of treatment were analyzed as a continuous variable. The study concluded that higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.