Elsevier

Journal of Hepatology

Volume 61, Issue 2, August 2014, Pages 219-227
Journal of Hepatology

Research Article
Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial

https://doi.org/10.1016/j.jhep.2014.04.004Get rights and content

Background & Aims

In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naïve patients infected with hepatitis C virus genotype 1.

Methods

CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naïve adults (⩽70 years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾5 log10 IU/ml) were randomized (2:1) to simeprevir 100 mg once-daily with peginterferon α-2a/ribavirin for 12 weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36 weeks, or to placebo with peginterferon α-2a/ribavirin for 12 weeks then peginterferon α-2a/ribavirin for 36 weeks.

Results

Overall, 183 patients were treated. Sustained virologic response 12 weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of simeprevir- and 61.7% of placebo-treated patients (p <0.0001 for stratum-adjusted between-group difference). Overall, 91.9% of simeprevir-treated patients met response-guided therapy criteria and completed treatment at week 24; sustained virologic response rate at 12 weeks in these patients was 92.0%. One simeprevir- (0.8%) and two placebo-treated patients (3.3%) experienced viral breakthrough; respective viral relapse rates were 7.6% and 30.6%. Overall adverse event profile in simeprevir-treated patients was comparable to that in patients who received peginterferon α-2a/ribavirin alone.

Conclusions

Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12 weeks after treatment end in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients.

Introduction

Japan has one of the highest rates of hepatitis C virus (HCV) infection worldwide, with around 2 million people estimated to be infected [1]. Of these, about 70% are infected with HCV genotype 1b, 20% with genotype 2a, and the remainder with genotype 2b or other genotypes. Hepatocellular carcinoma is a leading cause of cancer mortality in Japan, with approximately 70% of cases related to HCV infection [2].

The goal of chronic HCV infection treatment is virus eradication, to prevent progression to cirrhosis and hepatocellular carcinoma. Until recently, standard of care was combination therapy with peginterferon (PegIFN) and ribavirin (RBV) for 24–48 weeks [3], [4], resulting in sustained virologic response (SVR) in approximately 50% of patients [5], [6]. However, HCV genotype 1 appears less responsive to PegIFN-based therapy than other genotypes [7].

The development of direct-acting antiviral agents represents a major breakthrough in the treatment of chronic HCV infection. These have been shown to improve SVR rates when combined with PegIFN/RBV in treatment-naïve and treatment-experienced patients [8], [9]. Current Japanese guidelines recommend triple therapy with the HCV NS3/4A protease inhibitor (PI) telaprevir plus PegIFN/RBV for chronic genotype 1 HCV infection [10]. However, first-generation HCV PIs, such as telaprevir and boceprevir, are associated with two- or three-times daily dosing, the potential for adverse events (AEs) including anemia, rash, and renal dysfunction; and relatively rapid emergence of resistance in patients who do not achieve SVR [8], [9], [11], [12], [13].

Simeprevir (TMC435) is a potent, oral, once-daily (QD), HCV NS3/4A PI which has recently been approved in Japan [14]. In a Phase I study, simeprevir plasma exposure was found to be higher in healthy Japanese adult male volunteers than in healthy Caucasian volunteers [15]. Based on this finding, simeprevir doses of 50 and 100 mg QD were selected for use in further studies in Japan. A Phase II study in Japanese treatment-naïve patients with HCV genotype 1 infection and high viral load reported simeprevir (50 or 100 mg QD, for 12 or 24 weeks) in combination with PegIFNα-2a/RBV to be generally well tolerated and associated with improved SVR rates and shorter 24-week treatment duration in most patients [16]. The Clinical Optimization of New treatment strategy with TMC435 in Combination with peginterferon plus Ribavirin for Treatment-naïve and treatment-experienced patients infected with HCV genotype 1 (One; CONCERTO) studies were initiated to further explore efficacy and safety of simeprevir combined with PegIFN/RBV in patients with HCV genotype 1 infection in Japan. We present results of the CONCERTO-1 study (ClinicalTrials.gov: NCT01292239) in treatment-naïve patients.

Section snippets

Patients

Treatment-naïve male and female patients aged 20–70 years with documented chronic genotype 1 HCV infection and plasma HCV RNA ⩾5.0 log10 IU/ml at screening were eligible. Key exclusion criteria included liver cirrhosis, hepatic failure, any other liver disease of non-HCV etiology and co-infection with HIV-1, HIV-2, hepatitis B, or non-genotype 1 HCV. Additional exclusion criteria are summarized in the Supplementary data. All patients provided written informed consent before study entry.

Study design

This Phase

Study population

Overall, 223 patients were screened for study participation and 188 were randomized, and 183 received ⩾1 dose of study medication (123 received simeprevir and 60 received placebo) (Fig. 1). Eleven patients (6.0%) discontinued the study during follow-up (3.3% and 11.7% in the simeprevir and placebo groups, respectively). The most common reason for study discontinuation was withdrawal of consent. In the simeprevir group, 92.7% completed the treatment period, as did 75.0% in the placebo group.

Discussion

This study was undertaken to assess efficacy and safety of simeprevir in combination with PegIFNα-2a/RBV in treatment-naïve patients with chronic HCV genotype 1 infection and high viral load in Japan. A simeprevir dose of 100 mg with a 12 week duration for triple therapy was selected for use in this study based on results of a previous Phase II trial [16]. Oral once-daily treatment with simeprevir 100 mg for 12 weeks was associated with a significant improvement in SVR12 rate in this patient

Financial support

This study was funded by Janssen Pharmaceutical K.K. Writing and editorial support were provided by Complete Medical Communications and funded by Janssen Research & Development.

Conflict of interest

Drs Okanoue, Tsubouchi, Kumada, and Hayashi consult and advise Janssen Pharmaceuticals. Drs Ki, Komada, Seto, and Goto are employed by Janssen Pharmaceuticals.

Acknowledgments

The authors would like to thank all patients, their families, investigators, and their staff at the 37 study sites. The study sites are listed in the Supplementary data.

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