SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients

Abstract

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Study design. Treatment-naive patients were randomized to 12 or 24 weeks of faldaprevir plus pegylated interferon α-2a (PegIFN) and ribavirin (RBV), followed by PegIFN/RBV alone. Patients who achieved a maintained rapid virologic response (mRVR; HCV RNA below the lower limit of quantification [LLOQ;

FIG 2

Patient disposition. Footnotes: a, one patient experienced severe bone pain during PR lead-in and discontinued before receiving FDV; b, includes lack of efficacy and lost to follow-up. QD, once daily; PR, pegylated interferon α-2a and ribavirin; mRVR, maintained rapid virologic response (HCV RNA below the lower limit of quantification [LLOQ;

FIG 3

(A) Rapid virologic response (RVR), maintained rapid virologic response (mRVR), and sustained virologic response (SVR) rates by treatment group. (B) SVR rates in patients who achieved mRVR versus those who did not achieve mRVR. P values (two sided) were calculated using the Cochran-Mantel-Haenszel test, adjusted for genotype 1 subtype (1a or 1b). RVR, HCV RNA undetectable at week 4; mRVR, HCV RNA below the lower limit of quantification [LLOQ; <25 IU/ml] at week 4 and undetectable at weeks 8 and 12); SVR, HCV RNA undetectable at 24 weeks posttreatment.

FIG 4

Sustained virologic response (SVR) rates in relation to time taken to achieve undetectable HCV RNA. A shorter time to achieve undetectable HCV RNA was associated with higher likelihood of SVR.

FIG 5

Proportion of patients with undetectable HCV RNA at different time points. Through week 12, more patients in the 24-week group than in the 12-week group achieved undetectable HCV RNA.