A Study of Ritonavir-Boosted Danoprevir (RO5190591) in Combination With Pegasys and Ribavirin in Patients With Chronic Hepatitis C Genotype 1

• Safety and tolerability: Adverse events, ECG, laboratory parameters [ Time Frame: approximately 3 years ] [ Designated as safety issue: No ]
• Pharmacokinetics: Cmax, AUC, Cmin, Tmax, Cl, T1/2 [ Time Frame: Days 3-9 ] [ Designated as safety issue: No ]
• Antiviral activity: HCV RNA (COBAS Taqman HCV Test) [ Time Frame: from baseline to Day 28 ] [ Designated as safety issue: No ]

• Viral resistance development [ Time Frame: from baseline to Day 17 ] [ Designated as safety issue: No ]
• Effects on cytochrome P450(CYP)2C9 and 3A isozymes [ Time Frame: from baseline to Day 17 ] [ Designated as safety issue: No ]
• Virological response in prior null-responders [ Time Frame: from baseline to week 72 ] [ Designated as safety issue: No ]
• Comparison of pharmacokinetics and antiviral activity between treatment-naïve patients and prior null-responders to standard of care treatment [ Time Frame: approximately 3 years ] [ Designated as safety issue: No ]

This study will evaluate the efficacy, safety and tolerability of danoprevir (RO5190591) plus ritonavir as compared to danoprevir alone or placebo plus ritonavir in patients with chronic hepatitis C genotype 1 receiving Pegasys (peginterferon alfa-2a) and ribavirin. Patients in cohorts will be randomized to receive either oral doses of danoprevir, or danoprevir plus ritonavir, or placebo plus ritonavir. All patients will receive Pegasys (180mcg sc once weekly) plus ribavirin (1000-1200mg/day po), with the option to continue this treatment after completion of study drug treatment. Anticipated time on study treatment is up to 12 weeks.

• Drug: danoprevir
  oral doses
• Drug: ritonavir
  oral doses
• Drug: placebo
  oral doses
• Drug: peginterferon alfa-2a [Pegasys]
  180 mcg sc once weekly
• Drug: ribavirin
  1000-1200mg/day po

• Active Comparator: A
  Interventions:

  • Drug: danoprevir
  • Drug: peginterferon alfa-2a [Pegasys]
  • Drug: ribavirin
• Experimental: B
  Interventions:

  • Drug: danoprevir
  • Drug: ritonavir
  • Drug: peginterferon alfa-2a [Pegasys]
  • Drug: ribavirin
• Placebo Comparator: C
  Interventions:

  • Drug: ritonavir
  • Drug: placebo
  • Drug: peginterferon alfa-2a [Pegasys]
  • Drug: ribavirin

Inclusion Criteria:

• Adults, 18-65 years of age
• Chronic hepatitis C genotype 1
• HCV treatment naïve, or without sustained virologic response on prior PEG-INF/RBV treatment
• Body mass index (BMI) 18 - 35 kg/m2, inclusive; minimum weight 45 kg

Exclusion Criteria:

• Liver cirrhosis
• Decompensated liver disease or impaired liver function
• Medical condition associated with chronic liver disease other than chronic hepatitis C
• Positive for hepatitis B or HIV infection at screening
• History of alcohol consumption exceeding 2 standard drinks per day when averaged over the course of a given week