Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: A randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial

Stanislas Pol, Reem H. Ghalib, Vinod K. Rustgi, Claudia Martorell, Greg T. Everson, Harvey A. Tatum, Christophe Hézode, Joseph K. Lim, Jean Pierre Bronowicki, Gary A. Abrams, Norbert Bräu, David W. Morris, Paul J. Thuluvath, Robert W. Reindollar, Philip D. Yin, Ulysses Diva, Robert Hindes, Fiona McPhee, Dennis Hernandez, Megan Wind-RotoloEric A. Hughes, Steven Schnittman

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Background: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. Methods: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with. ClinicalTrials.gov, number. NCT00874770. Findings: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. Interpretation: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. Funding: Bristol-Myers Squibb.

Original languageEnglish (US)
Pages (from-to)671-677
Number of pages7
JournalThe Lancet infectious diseases
Volume12
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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