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

The Lancet  Volume 12, Issue 9, September 2012, Pages 671–677

Articles

Dr Prof Stanislas Pol, MD^a,, Prof Reem H Ghalib, MD^b, Prof Vinod K Rustgi, MD^c, Prof Claudia Martorell, MD^d, Prof Greg T Everson, MD^e, Prof Harvey A Tatum, MD^f, Prof Christophe Hézode, MD^g, Prof Joseph K Lim, MD^h, Prof Jean-Pierre Bronowicki, MDⁱ, Prof Gary A Abrams, MD^j, Prof Norbert Bräu, MD^k, Prof David W Morris, DO^l, Prof Paul J Thuluvath, MD^m, Prof Robert W Reindollar, MDⁿ, Philip D Yin, MD^o, Ulysses Diva, PhD^o, Robert Hindes, MD^p, Fiona McPhee, PhD^o, Dennis Hernandez, PhD^o, Megan Wind-Rotolo, PhD^q, Eric A Hughes, MD^q, Steven Schnittman, MD^o

a Hôpital Cochin, Paris, France
b Texas Clinical Research Institute, Arlington, TX, USA
c Metropolitan Research, Fairfax, VA, USA
d The Research Institute, Springfield, MA, USA
e University of Colorado Denver, Aurora, CO, USA
f Options Health Research, Tulsa, OK, USA
g Hôpital Henri Mondor, Créteil, France
h Yale University School of Medicine, New Haven, CT, USA
i INSERM 954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre Les Nancy, France
j Alabama Liver and Digestive Specialists, Montgomery, AL, USA
k James J Peters VA Medical Center, Bronx, NY, USA
l Healthcare Research Consultants, Tulsa, OK, USA
m Mercy Medical Center, Baltimore, MD, USA
n Carolinas Center for Liver Disease, Statesville, NC, USA
o Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA
p Gilead Sciences, Foster City, CA, USA
q Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA

Summary

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.

Source