A Placebo-Controlled, Multicenter, Double-Blind, Phase 2 Randomized Trial of the Pan-Caspase Inhibitor Emricasan in Patients with Acutely Decompensated Cirrhosis
التفاصيل البيبلوغرافية
العنوان:
A Placebo-Controlled, Multicenter, Double-Blind, Phase 2 Randomized Trial of the Pan-Caspase Inhibitor Emricasan in Patients with Acutely Decompensated Cirrhosis
Background Cirrhosis and acute-on-chronic liver failure (ACLF) are associated with systemic inflammation, and caspase-mediated hepatocyte cell death. Emricasan is a novel, pan-caspase inhibitor. Aims of this study were to assess the pharmacokinetics, pharmacodynamics, safety and clinical outcomes of emricasan in acute decompensation (AD) of cirrhosis. Methods This was a phase 2, multicentre, double-blind, randomized trial. The primary objective was to evaluate the pharmacokinetics, pharmacodynamics and safety of emricasan in patients with cirrhosis presenting with AD and organ failure. AD was defined as an acute decompensating event ≤6 weeks’ duration. Patients were randomized proportionately to emricasan 5 mg bid, emricasan 25 mg bid, emricasan 50 mg bid or placebo. Treatment was continued to 28 days, or voluntary discontinuation. Results Twenty-three subjects were randomized, of whom 21 were dosed (placebo n = 4; 5 mg n = 5; 25 mg n = 7; 50 mg n = 5). Pharmacokinetic data showed 5 mg dose was associated with low plasma levels ( Conclusion This study demonstrates that emricasan is safe and well tolerated in advanced liver disease. However, this study fails to provide proof-of-concept support for caspase inhibition as a treatment strategy for ACLF. Trial registration EudraCT 2012-004245-33
