A Study of RO5024048 in Combination With Ritonavir-Boosted Danoprevir and Pegasys/Copegus in Patients With Chronic Hepatitis C Genotype 1 Who Have Failed Prior HCV Protease Inhibitor Treatment

Study Overview
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Brief Summary
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This randomized, double blind, phase II study will evaluate the efficacy and safety of two doses of RO5024048 in combination with ritonavir-boosted danoprevir and Pegasys (peginterferon alpha-2a) and Copegus (ribavirin) in patients who failed a prior protease inhibitor containing regimen with or without pegylated interferon. Patients will be randomized to receive either a 2-week lead-in of RO5024048 (1500 mg or 1000 mg orally twice daily) in combination with Pegasys (180 mcg subcutaneously weekly) and Copegus (1000 mg or 1200 mg orally daily) followed by 24 weeks of therapy with RO5024048 in combination with danoprevir (100 mg orally twice daily) plus ritonavir (100 mg orally twice daily) and Pegasys and Copegus (QUAD therapy), or 24 weeks of therapy with RO5024048 in combination with danoprevir plus ritonavir and Pegasys and Copegus (QUAD therapy). Anticipated time on study treatment is 24 or 26 weeks, with a treatment-free follow-up of 24 weeks.

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: RO5024048
* Drug: RO5024048
* Drug: danoprevir
* Drug: peginterferon alfa-2a [Pegasys]
* Drug: ribavirin [Copegus]
* Drug: ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Hepatitis C genotype 1 infection Serum HCV quantifiable by Roche COBAS TaqMan HCV Test v2.0 Liver biopsy (within 24 months) or Fibroscan (within 12 months) before first administration of study drug consistent with chronic hepatitis C and demonstrating absence of liver cirrhosis Documented failed prior treatment with protease inhibitor (evidenced by viral breakthrough or partial response while on treatment or relapse after treatment), including documentation on treatment with other direct-acting antiviral agents and other HCV antiviral treatment Patients must have discontinued prior HCV treatment at least 24 weeks prior to first dose of study drug in this trial Exclusion Criteria: Infection with any HCV genotype other than genotype 1 Evidence of any variants associated with protease inhibitor resistance at screening Body mass index (BMI) <18 or >/=36 kg/m2 Positive for hepatitis A or hepatitis B infection Use of any systemic antiviral therapy with perceived activity against HCV </=1 month prior to first dose of study drug History or evidence of a medical condition associated with chronic liver disease other than chronic hepatitis C Pregnant or breastfeeding women Males with female partners who are pregnant History of immunologically mediated disease; patients with rheumatoid arthritis requiring only intermittent non-steroidal anti-inflammatory medications or with celiac disease will be allowed History or evidence of decompensated liver disease History or evidence of renal disease; patients with history of nephrolithiasis will be allowed Uncontrolled Type 1 or 2 diabetes History or evidence of chronic pulmonary disease associated with functional limitation History of severe cardiac disease History of any neoplastic disease within the last 5 years, except for localized or in situ carcinoma of the skin (e.g. basal or squamous cell carcinoma) Evidence of excessive alcohol, drug or substance abuse (excluding marijuana use) within 1 year of the first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1000 mg 24 weeks<br> | Drug: RO5024048<br>* 1000 mg po bid, 24 or 26 weeks<br>Drug: danoprevir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg sc qw, 24 or 26 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg po daily, 24 or 26 weeks<br>|
| Active Comparator: 1000 mg 26 weeks<br> | Drug: RO5024048<br>* 1000 mg po bid, 24 or 26 weeks<br>Drug: danoprevir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg sc qw, 24 or 26 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg po daily, 24 or 26 weeks<br>Drug: ritonavir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>|
| Experimental: 1500 mg 24 weeks<br> | Drug: RO5024048<br>* 1500 mg po bid, 24 or 26 weeks<br>Drug: danoprevir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg sc qw, 24 or 26 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg po daily, 24 or 26 weeks<br>Drug: ritonavir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>|
| Experimental: 1500 mg 26 weeks<br> | Drug: RO5024048<br>* 1500 mg po bid, 24 or 26 weeks<br>Drug: danoprevir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg sc qw, 24 or 26 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg po daily, 24 or 26 weeks<br>Drug: ritonavir<br>* 100 mg po bid, Weeks 1 to 24 or Weeks 3 to 26<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response (defined as unquantifiable serum HCV RNA) 12 weeks after treatment (SVR-12) |  | approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response 4 weeks after treatment (SVR-4) |  | approximately 2 years | 
| Sustained virologic response 24 weeks after treatment (SVR-24) |  | approximately 2 years | 
| Change in serum HCV RNA levels |  | from baseline to Week 12 | 
| Virologic response over time |  | from baseline to 24 weeks after treatment | 
| Correlation between trough concentrations of RO4995855 and virologic response |  | approximately 2 years | 
| Incidence of direct-acting antiviral (DAA) resistance, including re-emergence of protease inhibitor resistant virus |  | approximately 2 years | 
| Safety: Incidence of adverse events |  | approximately 2 years |