GS 5885 Administered Concomitantly With GS-9451, Tegobuvir and Ribavirin (RBV) in Chronic Genotype 1 Hepatitis C Virus (HCV) Infection

• Safety and tolerability [ Time Frame: through 24 weeks of off-treatment follow-up ] [ Designated as safety issue: Yes ]
  To evaluate the safety and tolerability of 30 mg or 90 mg GS-5885 when given with GS-9451, Tegobuvir and RBV for 12 or 24 weeks. Safety endpoints will be analyzed by the number and percent of subjects with events or abnormalities for categorical values or 8-number summary (n, mean, standard deviation, median, Q1, Q3, minimum, maximum) for continuous data by treatment group.
• HCV RNA < Lower Limit Of Quantification [ Time Frame: Weeks 1, 2, 4, 12 and 24 ] [ Designated as safety issue: No ]
  To evaluate the antiviral efficacy at Weeks 1, 2, 4, 12 and 24, as measured by the rates of HCV RNA < LLoQ and viral breakthrough and relapse.
• Rescue Therapy Substudy SVR [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  To evaluate the antiviral efficacy (as defined by SVR) of the addition of pegylated interferon (PEG) for 24 weeks to GS-5885, GS-9451, tegobuvir and RBV in subjects who experience viral breakthrough on treatment.
• Emergence of viral resistance [ Time Frame: 12 or 24 weeks ] [ Designated as safety issue: No ]
  To evaluate the emergence of viral resistance during treatment with GS-9451, Tegobuvir and RBV when given with 30 mg or 90 mg GS-5885 for 12 or 24 weeks.
• Viral dynamics of GS-5885, GS-9451 and Tegobuvir when administered in combination with RBV [ Time Frame: Through Week 2 of therapy ] [ Designated as safety issue: No ]
  HCV RNA levels, pharmacokinetics and viral sequencing
• Pharmacokinetics of GS-5885, GS-9451 and Tegobuvir when administered in combination with RBV [ Time Frame: Through Week 2 of therapy ] [ Designated as safety issue: No ]

  Pharmacokinetics (Cmax, Tmax, Clast, Tlast, Ctau, λz, AUCtau, and T½) will be listed

  and summarized for GS-5885, GS-9451 and Tegobuvir using descriptive statistics (e.g.,

  sample size, arithmetic mean, geometric mean, % coefficient of variation, standard deviation,

  median, minimum, and maximum). Plasma concentrations of the study drug over time will be

  summarized using descriptive statistics

• Safety and tolerability [ Time Frame: through 24 weeks of off-treatment follow-up ] [ Designated as safety issue: Yes ]
  To evaluate the safety and tolerability of 30 mg or 90 mg GS-5885 when given with GS-9451, tegobuvir and RBV for 12 or 24 weeks. Safety endpoints will be analyzed by the number and percent of subjects with events or abnormalities for categorical values or 8-number summary (n, mean, standard deviation, median, Q1, Q3, minimum, maximum) for continuous data by treatment group.
• HCV RNA < Lower Limit Of Quantification [ Time Frame: Weeks 1, 2, 4, 12 and 24 ] [ Designated as safety issue: No ]
  To evaluate the antiviral efficacy at Weeks 1, 2, 4, 12 and 24, as measured by the rates of HCV RNA < LLoQ and viral breakthrough and relapse.
• Rescue Therapy Substudy SVR [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  To evaluate the antiviral efficacy (as defined by SVR) of the addition of pegylated interferon (PEG) for 24 weeks to GS-5885, GS-9451, tegobuvir and RBV in subjects who experience viral breakthrough on treatment.
• Emergence of viral resistance [ Time Frame: 12 or 24 weeks ] [ Designated as safety issue: No ]
  To evaluate the emergence of viral resistance during treatment with GS-9451, tegobuvir and RBV when given with 30 mg or 90 mg GS-5885 for 12 or 24 weeks.
• Viral dynamics of GS-5885, GS-9451 and tegobuvir when administered in combination with RBV [ Time Frame: Through Week 2 of therapy ] [ Designated as safety issue: No ]
  HCV RNA levels, pharmacokinetics and viral sequencing
• Pharmacokinetics of GS-5885, GS-9451 and tegobuvir when administered in combination with RBV [ Time Frame: Through Week 2 of therapy ]

  Pharmacokinetics (Cmax, Tmax, Clast, Tlast, Ctau, λz, AUCtau, and T½) will be listed

  and summarized for GS-5885, GS-9451 and Tegobuvir using descriptive statistics (e.g.,

  sample size, arithmetic mean, geometric mean, % coefficient of variation, standard deviation,

  median, minimum, and maximum). Plasma concentrations of the study drug over time will be

  summarized using descriptive statistics

The purpose of this phase 2 study is to determine whether 30 mg or 90 mg of GS-5885 when given with GS-9451, Tegobuvir and Ribavirin (RBV) for 12 or 24 weeks is effective, safe and tolerable in the treatment of Chronic Genotype 1 HCV Infection.

• Drug: GS-5885
  tablet, 30 mg QD
• Drug: Tegobuvir
  capsule, 30 mg BID
• Drug: GS-9451
  tablet, 200 mg QD
• Drug: ribavirin tablet
  (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID)
• Drug: GS-5885
  tablet, 90 mg QD

• Active Comparator: Arm 1
  GS-5885, GS-9451 and Tegobuvir in combination with ribavirin (Copegus®) for 24 weeks.
  Interventions:

  • Drug: GS-5885
  • Drug: Tegobuvir
  • Drug: GS-9451
  • Drug: ribavirin tablet
• Active Comparator: Arm 2
  GS-5885, GS-9451 and Tegobuvir in combination with ribavirin (Copegus®) for 12 or 24 weeks.
  Interventions:

  • Drug: Tegobuvir
  • Drug: GS-9451
  • Drug: ribavirin tablet
  • Drug: GS-5885

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

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 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