November 6, 2013

Gastroenterology

Article in Press

Stefan Zeuzem,Thomas Berg,Edward Gane,Peter Ferenci,Graham R. Foster,Michael W. Fried,Christophe Hezode,Gideon M. Hirschfield, Ira Jacobson,Igor Nikitin,Paul J. Pockros,Fred Poordad,Jane Scott,Oliver Lenz,Monika Peeters,Vanitha Sekar,Goedele De Smedt, Rekha Sinha,Maria Beumont-Mauviel

Received 4 July 2013; received in revised form 24 October 2013; accepted 29 October 2013. published online 04 November 2013.
Accepted Manuscript

Abstract

Background & Aims

Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in Phase III trials for chronic hepatitis C virus (HCV) infection. We performed a Phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV.

Methods

We analyzed data from patients who did not respond (null response), had a partial response, or relapsed following treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n=396), or placebo plus PegIFN and RBV for 48 weeks (n=66). All patients were followed for 24 weeks after planned end of treatment; the primary endpoint was the proportion of patients with sustained virologic response (undetectable HCV RNA) at that timepoint (SVR24).

Results

Overall, SVR24 rates were significantly higher in the groups given simeprevir than those given placebo (61%–80% vs 23%;P<.001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%–59% vs 19%; prior partial response, 48%–86% vs 9%; prior relapse, 77%–89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo.

Conclusions

In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR24 compared to patients given placebo, PegIFN, and RBV and was generally well tolerated.

ClinicalTrials.gov number: NCT00980330

Keywords: direct-acting antivirals, DAA, clinical trial, SVR24

Abbreviations: AE, adverse event, ASPIRE, Antiviral STAT-C Protease Inhibitor Regimen in Experienced patients, AUC, area under the curve, BMI, Body Mass Index, EOT, End of treatment, FSS, Fatigue Severity Scale, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IC50, median inhibitory concentration, LLOQ, lower limit of quantification, PegIFN, Peginterferon-α2a, PegIFN-α, Peginterferon-α,PILLAR, Protease Inhibitor TMC435 study assessing optimaL dose and duration as once-daiLy Antiviral Regimen, QD, once daily, RBV,ribavirin, RVR, rapid virologic response, SMV, simeprevir, SVR, sustained virologic response, SVR24, sustained virologic response at 24 weeks after the planned end of treatment, ULN, upper limit of normal

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