A Study of Response-Guided Duration of Combination Therapy With GS-9451, Pegasys® and Copegus® With and Without Tegobuvir (GS-9190) in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C

• Safety and tolerability of therapy [ Time Frame: Through treatment period and 24 weeks of off-treatment follow-up ] [ Designated as safety issue: Yes ]
  Safety and tolerability of therapy as measured by frequency of laboratory abnormalities, reported adverse events, and discontinuations due to adverse events
• Emergence of viral resistance following initiation of therapy with GS 9190 and GS 9451 [ Time Frame: Through treatment period, 24 weeks of off-treatment follow-up, and up to 48 weeks of follow-up in the Resistance Registry Substudy ] [ Designated as safety issue: No ]
• Viral dynamics and steady state pharmacokinetics [ Time Frame: Through Week 4 of therapy ] [ Designated as safety issue: No ]
  Viral dynamics and steady state pharmacokinetics of GS 9190 and GS 9451 when administered in combination with PEG and RBV; measured by HCV RNA levels and plasma concentrations of GS-9190 and GS-9451 over time
• Durability of response in subjects who achieve SVR [ Time Frame: 36 months following Week 72 ] [ Designated as safety issue: No ]

This phase 2b study will evaluate the efficacy and safety of 16 and 24 weeks of a 4-drug regimen with GS-9451 and Tegobuvir and 24 weeks of a 3-drug regimen of GS-9451 without Tegobuvir, all with Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®).

• Drug: Tegobuvir (GS-9190)
  Tegobuvir (GS-9190) capsule, 30 mg BID
• Drug: GS-9451
  GS-9451 tablet, 200 mg QD
• Biological: Pegasys®
  peginterferon alfa-2a (solution for injection) 180 µg/week
• Drug: Copegus®
  ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID)
• Drug: Tegobuvir placebo
  placebo matching Tegobuvir (GS-9190) capsule BID
• Drug: GS-9451 placebo
  placebo matching GS-9451 tablet QD
• Drug: Copegus®
  ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID); tablet

• Active Comparator: Arm 1
  GS-9451 and Tegobuvir (GS-9190) in combination with Pegasys® and Copegus® for 16 or 24 weeks; Pegasys® and Copegus® may be continued for up to 48 weeks total duration depending on individual response to therapy
  Interventions:

  • Drug: Tegobuvir (GS-9190)
  • Drug: GS-9451
  • Biological: Pegasys®
  • Drug: Copegus®
• Active Comparator: Arm 2
  GS-9451 (active) and Tegobuvir (GS-9190) placebo in combination with Pegasys® and Copegus® for 24 weeks; Pegasys® and Copegus® may be continued for up to 48 weeks total duration depending on individual response to therapy
  Interventions:

  • Drug: GS-9451
  • Drug: Tegobuvir placebo
  • Biological: Pegasys®
  • Drug: Copegus®
• Placebo Comparator: Arm 3
  Placebo matching Tegobuvir (GS-9190) and GS-9451 in combination with Pegasys® and Copegus® for 24 weeks; Pegasys® and Copegus® will be continued for up to 48 weeks total duration
  Interventions:

  • Drug: Tegobuvir placebo
  • Drug: GS-9451 placebo
  • Biological: Pegasys®
  • Drug: Copegus®

Inclusion Criteria:

• Adult subjects 18 to 70 years of age
• Chronic HCV infection for at least 6 months prior to Baseline (Day 1)
• Liver biopsy results (performed no more than 2 years prior to Screening) indicating the absence of cirrhosis
• Monoinfection with HCV genotype 1a or 1b
• HCV treatment-naïve
• Body mass index (BMI) between 18 and 36 kg/m2
• Creatinine clearance ≥ 50 mL/min
• Subject agrees to use highly effective contraception methods if female of childbearing potential or sexually active male.
• Screening laboratory values within defined thresholds for ALT, AST, leukopenia, neutropenia, anemia, thrombocytopenia, thyroid stimulating hormone (TSH), potassium, magnesium

Exclusion Criteria:

• Autoimmune disease
• Decompensated liver disease or cirrhosis
• Poorly controlled diabetes mellitus
• Severe psychiatric illness
• Severe chronic obstructive pulmonary disease (COPD)
• Serological evidence of co-infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or another HCV genotype
• Suspicion of hepatocellular carcinoma or other malignancy (with exception of certain skin cancers)
• History of hemoglobinopathy
• Known retinal disease
• Subjects who are immunosuppressed
• Subjects with known, current use of amphetamines, cocaine, opiates (i.e., morphine, heroin), methadone, or ongoing alcohol abuse
• Subjects who are on or are expected to be on a potent cytochrome P450 (CYP) 3A4 or Pgp inhibitor, or a QT prolonging medication within 2 weeks of Baseline (Day 1) or during the study
• Subjects must have no history of clinically significant cardiac disease, including a family history of Long QT syndrome, and no relevant electrocardiogram (ECG) abnormalities at screening