Phase III Hallmark DUAL: ASV+DCV (Nulls/Partials, Intolerants/Ineligibles. Naives)

• Proportion of treated subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for subjects who are intolerant or ineligible to P/R [ Time Frame: Post-treatment Week 12 ] [ Designated as safety issue: No ]
• On treatment safety, as measured by frequency of Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) [ Time Frame: End of Treatment (up to 48 weeks) plus 7 days ] [ Designated as safety issue: Yes ]
• Differences in rates of selected grade 3-4 laboratory abnormalities during the first 12 weeks between treatments (ASV + DCV vs PBO) for naive subjects [ Time Frame: Up to first 12 weeks ] [ Designated as safety issue: No ]
• Proportion of genotype 1b subjects with SVR12 (HCV RNA < LOQ at post treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene for each cohort [ Time Frame: Post-treatment Week 12 ] [ Designated as safety issue: No ]
• Proportion of genotype 1b subjects with HCV RNA undetectable [ Time Frame: At weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12 [eRVR]; EOT (up to 24 weeks), post-treatment Week 12, or post-treatment Week 24 for each cohort ] [ Designated as safety issue: No ]
  eRVR = Extended rapid virologic response, EOT = End of treatment
• Proportion of genotypes 1b subjects with HCV RNA < LOQ [ Time Frame: At weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12 [VR(4&12)]; EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each cohort ] [ Designated as safety issue: No ]
• Proportion of subjects with anemia [ Time Frame: At 12 weeks post-treatment ] [ Designated as safety issue: No ]
• Proportion of subjects with rash [ Time Frame: At 12 weeks post-treatment ] [ Designated as safety issue: No ]

• Proportion of treated subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for subjects who are intolerant or ineligible to P/R [ Time Frame: Post-treatment Week 12 ] [ Designated as safety issue: No ]
• On treatment safety, as measured by frequency of Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) [ Time Frame: End of Treatment (up to 48 weeks) plus 7 days ] [ Designated as safety issue: Yes ]
• Differences in rates of selected grade 3-4 laboratory abnormalities during the first 12 weeks between treatments (ASV + DCV vs PBO) for naive subjects [ Time Frame: Up to first 12 weeks ] [ Designated as safety issue: No ]
• Proportion of genotype 1b subjects with SVR12 (HCV RNA < LOQ at post treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene for each cohort [ Time Frame: Post-treatment Week 12 ] [ Designated as safety issue: No ]
• Proportion of genotype 1b subjects with HCV RNA undetectable [ Time Frame: At weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12 [eRVR]; EOT (up to 24 weeks), post-treatment Week 12, or post-treatment Week 24 for each cohort ] [ Designated as safety issue: No ]
  eRVR = Extended rapid virologic response, EOT = End of treatment
• Proportion of genotypes 1b subjects with HCV RNA < LOQ [ Time Frame: At weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12 [VR(4&12)]; EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each cohort ] [ Designated as safety issue: No ]

The purpose of this study is to estimate efficacy, as determined by the proportion of subjects with Sustained virologic response at post-treatment Week 12 (SVR12), defined as Hepatitis C virus (HCV) Ribonucleic acid (RNA) < Limit of quantitation (LOQ) at post-treatment Week 12, for subjects who are prior null or partial responders to P/R or who are treatment-naive.

Allocation: Treatment naive cohort: Randomized Controlled Trial, Null/partial responder and intolerant/ineligible cohorts: N/A (Single arm study)

Masking: Treatment naive cohort: Double Blind, Null/partial responder and intolerant/ineligible cohorts: Open

Intervention Model: Treatment naive cohort: Parallel, Null/partial responder and intolerant/ineligible cohorts: Single group

• Drug: Asunaprevir (ASV)
  Capsule, Oral, 100 mg, Twice daily, 24 Weeks
  Other Name: BMS-650032 (ASV)
• Drug: Daclatasvir (DCV)
  Tablet, Oral, 60 mg, Once daily, 24 Weeks
  Other Name: BMS-790052 (DCV)
• Drug: PBO matching ASV
  Capsule, Oral, 0 mg, Twice daily, 12 Weeks
• Drug: Placebo (PBO) matching DCV
  Tablet, Oral, 0 mg, Once daily, 12 Weeks
• Drug: Pegylated-interferon alfa 2a (PegIFN)
  Injection, subcutaneously (SC), 180 mcg/0.5 mL, once weekly, 24 weeks
  Other Name: Pegasys
• Drug: Ribavirin (RBV)
  Tablet, Oral, 1000 mg / 1200 mg (depending on subject weight), twice daily, 24 weeks
  Other Name: Copegus

• Experimental: Arm 1: Null or Partial Responder to P/R (ASV + DCV)
  Subjects meeting prespecified rescue criteria in the null or partial responder cohort may have therapeutic rescue instituted with QUAD regimen (QUAD= ASV + DCV + P/R)
  Interventions:

  • Drug: Asunaprevir (ASV)
  • Drug: Daclatasvir (DCV)
  • Drug: Pegylated-interferon alfa 2a (PegIFN)
  • Drug: Ribavirin (RBV)
• Experimental: Arm 2: Intolerant to or Ineligible for P/R (ASV + DCV)
  Interventions:

  • Drug: Asunaprevir (ASV)
  • Drug: Daclatasvir (DCV)
• Experimental: Arm 3: Treatment naive (ASV + DCV / Matching PBO)

  [Subjects will receive ASV + DCV for 24 weeks] or [placebo (PBO) matching ASV + PBO matching DCV for 12 weeks followed by ASV + DCV for 24 weeks in protocol AI444026]

  Subjects meeting prespecified rescue criteria in the treatment naive cohort may have therapeutic rescue instituted with QUAD regimen (QUAD= ASV + DCV + P/R)

  Interventions:

  • Drug: Asunaprevir (ASV)
  • Drug: Daclatasvir (DCV)
  • Drug: PBO matching ASV
  • Drug: Placebo (PBO) matching DCV
  • Drug: Pegylated-interferon alfa 2a (PegIFN)
  • Drug: Ribavirin (RBV)

Inclusion Criteria:

• Males and females, ≥ 18 years of age
• HCV Genotype 1b who previously failed treatment with peginterferon alfa and ribavirin, classified as previous null or partial responders based on previous therapy, OR intolerant or ineligible to P/R due to neutropenia, anemia, depression or thrombocytopenia with cirrhosis, OR treatment naive
• HCV RNA ≥ 10,000 IU/mL
• Seronegative for Human immunodeficiency virus (HIV) and Hepatitis B surface antigen (HBsAg)
• Subjects with compensated cirrhosis are permitted (compensated cirrhotics are capped at approximately 25% of treated population)

Exclusion Criteria:

• Prior treatment of HCV with HCV direct acting antiviral (DAA)
• Evidence of a medical condition contributing to chronic liver disease other than HCV
• Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy
• Diagnosed or suspected hepatocellular carcinoma or other malignancies
• Uncontrolled diabetes or hypertension