TY - JOUR
T1 - Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection
T2 - A randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial
AU - Pol, Stanislas
AU - Ghalib, Reem H.
AU - Rustgi, Vinod K.
AU - Martorell, Claudia
AU - Everson, Greg T.
AU - Tatum, Harvey A.
AU - Hézode, Christophe
AU - Lim, Joseph K.
AU - Bronowicki, Jean Pierre
AU - Abrams, Gary A.
AU - Bräu, Norbert
AU - Morris, David W.
AU - Thuluvath, Paul J.
AU - Reindollar, Robert W.
AU - Yin, Philip D.
AU - Diva, Ulysses
AU - Hindes, Robert
AU - McPhee, Fiona
AU - Hernandez, Dennis
AU - Wind-Rotolo, Megan
AU - Hughes, Eric A.
AU - Schnittman, Steven
N1 - Funding Information:
SP has received research grants from Bristol-Myers Squibb, Gilead, Merck/Schering-Plough, and Roche; and consulting or lecture fees from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck/Schering-Plough, Novartis, Roche, and Tibotec. RHG has received research grants from Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Debio, Genentech, Gilead, Inhibitex, Pharmasset, Tibotec, Vertex, and Zymogenetics (Bristol-Myers Squibb). VKR received research grants from Bristol-Myers Squibb for this study. CM has received research grants from Abbott, Bristol-Myers Squibb, Gilead, and Novartis; and lecture fees from Abbott, Bristol-Myers Squibb, and Gilead. GTE received a research grant from Bristol-Myers Squibb (administered by the University of Colorado Denver) for this study; and has served on advisory boards for Bristol-Myers Squibb. JKL has received research grants from Bristol-Myers Squibb, Gilead, GlobeImmune, Roche/Genentech, Tibotec, and Vertex; and consulting fees from Bristol-Myers Squibb, Gilead, Merck, and Vertex. J-PB has received consulting fees from Bristol-Myers Squibb, Merck, Boehringer Ingelheim, Novartis, Roche, Gilead, and Janssen. PJT received research grants from Bristol-Myers Squibb for this study. RWR has received research grants from Abbott, Bristol-Myers Squibb, Merck, Novartis, Pharmasset, and Tibotec; and lecture fees from Merck and Vertex. PDY, UD, FM, DH, MW-R, EAH, and SS are employees of Bristol-Myers Squibb. HAT, CH, GAA, NB, DWM, and RH declare that they have no conflicts of interest.
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
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U2 - 10.1016/S1473-3099(12)70138-X
DO - 10.1016/S1473-3099(12)70138-X
M3 - Article
C2 - 22714001
AN - SCOPUS:84865285928
VL - 12
SP - 671
EP - 677
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
SN - 1473-3099
IS - 9
ER -