The amendment INT-2 included the following changes: Investigators had suggested to expand the study to include additional patient populations, in particular patients who had less advanced liver fibrosis (corresponding to METAVIR F0 F2), those who had hepatitis C virus (HCV) genotype 4, and those who had human immunodeficiency virus (HIV) or HCV coinfection. For both patient populations, interferon (IFN) -free options were still limited either due to restricted access or to lack of data. Both simeprevir and daclatasvir have individually shown to be active against HCV genotype 4 in Phase 3 clinical studies with pegylated interferon (PegIFN) and ribavirin (RBV), and are approved for the treatment of adult patients with HCV genotype 4. Increasing evidence indicated that the efficacy and safety of IFN free therapy was similar in HCV-infected patients with or without HIV coinfection. Hepatitis C virus therapy in HIV-/HCV-coinfected patients therefore had to follow the same treatment recommendations as in mono-infected patients, provided that potential drug interactions between HIV and HCV treatments were considered. Patients who had mild fibrosis, HCV genotype 4, and/or HCV/HIV coinfection continue to be under treated patient populations to understand the efficacy and safety of treatment with simeprevir in combination with daclatasvir. Additionally, the period after the end of therapy during which subjects were required to adhere to contraception requirements and sperm donation restrictions was extended, based on nonclinical embryotoxicity and teratogenicity information for daclatasvir.

The amendment INT-3 included the following changes: 1) Sponsor’s decision to discontinue Cohort 2 (METAVIR F0-F2 treatment-naive subjects who had genotype 1b infection) due to prompted concern that viral breakthrough could also be observed in subjects with HCV genotype 1b infection and mild-to-moderate fibrosis because Viral breakthroughs were observed in the early phase of Cohort 1 (METAVIR F3/F4 treatment naïve subjects with HCV genotype 1b infection), 2) Discontinuation of Cohort 3 due to the observed cases of viral breakthrough in a HCV genotype 1b population without baseline mutations L31M/V and Y93H, it could no longer be excluded with certainty that viral breakthrough could also be observed in HCV genotype 4, 3) Since no subjects with HIV were enrolled, information related to inclusion of HIV subjects, including concomitant therapy allowed, was no longer necessary, 4) collection of blood samples and analyses of pharmacokinetics, HIV viral load, and efficacy related to HIV and combination antiretroviral therapy (cART) were not collected/performed at time points after screening, 5) Extended required wash-out period for amiodarone to 120 days prior to baseline due its long half life, 6) Physical examination data were not recorded on the electronic case report form (eCRF); therefore no analyses of the data were performed, 7) clarified statistical methods for the primary analysis for Cohort 1, 8) Minor errors were noted or minor editorial changes made.