Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks

Abstract

Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated.

Fig. 1

Study flow chart. In this randomised, double-blind, placebo-controlled study, glycyrrhizin was administered intravenously 5×/or 3×/week, or placebo was injected 5×/week for 12 weeks to 379 patients. This double-blind phase was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks.

Fig. 2

Study design and patient disposition.

Fig. 3

Time course of serum ALT-levels during the study. N Number of patients; ALT alanine aminotransferase, GL glycyrrhizin. ALT values for total dose were analysed by stratification of 6 sub-groups of all study regimens. Four sub-groups receiving GL from week 0 (5×/5× GL, 5×/3× GL, 3×/5× GL, 3×/3× GL) showed an immediate decrease in ALT values (mean) compared to the two placebo arms. There was no dose dependent effect on ALT reduction among the four groups receiving GL throughout the study assessed at week 12 and week 52 (reduction range: 76–96%). The two placebo arms showed subsequently a decrease in mean ALT levels once they were switched to either 5× GL/week or 3× GL/week in the open phase. After switching to GL, the response rate became similar to the other 4 sub-groups (81% under GL, 48% under placebo).