A Study of Ritonavir-Boosted Danoprevir and RO5024048 in Different Combinations in Null Responder or Treatment-Naïve Patients With Chronic Hepatitis C and Compensated Cirrhosis

Study Overview
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Brief Summary
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This open-label, parallel cohort study will evaluate the safety, pharmacokinetics and antiviral activity of ritonavir-boosted danoprevir in combination with Pegasys (peginterferon alfa-2a) and ribavirin in treatment-naïve patients, and with RO5024048 added to the combination treatment in prior null responder patients with chronic hepatitis C genotype 1 or 4 and compensated cirrhosis. All patients will receive danoprevir 100 mg orally twice daily (bid) , ritonavir 100 mg orally bid, Pegasys 180 mcg subcutaneously weekly and ribavirin 1000-1200 mg/kg/day orally. Prior non-responders will receive RO5024048 1000 mg orally bid additionally. Anticipated time on study treatment is 24 weeks.

Official Title
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A Study to Evaluate Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Ritonavir-Boosted DANOPREVIR and RO5024048 in Different Combinations in Null Responder or Treatment Naïve Patients With Chronic Hepatitis C and Compensated Cirrhosis

Conditions
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Hepatitis C, Chronic

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, 18 to 65 years of age inclusive Chronic hepatitis C, genotype 1 or 4 Cohort 1: Treatment-naïve for hepatitis C Cohort 2: Prior null responder to treatment with approved doses of pegylated interferon plus ribavirin Liver biopsy confirming cirrhosis Compensated cirrhosis (Child-Pugh A) Exclusion Criteria: Pregnant or lactating women or male partners of women who are pregnant History or presence of decompensated liver disease (ascites, hepatic encephalopathy, hepatocellular carcinoma, or bleeding esophageal varices) Cohort 2: Patients who discontinued previous pegylated interferon plus ribavirin treatment due to reasons other than null response History of clinically significant cardiovascular or cerebrovascular disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination without RO5024048<br>Ritonavir-boosted danoprevir in combination with Pegasys (peginterferon alfa-2a) and ribavirin in treatment-naïve patients | Drug: danoprevir<br>* 100 mg orally bid, 24 weeks<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg weekly, 24 weeks<br>Drug: ribavirin<br>* 1000-1200 mg/kg/day orally in two divided doses, 24 weeks<br>Drug: ritonavir<br>* 100 mg orally bid, 24 weeks<br>|
| Experimental: Combination with RO5024048<br>RO5024048 added to the combination treatment (ritonavir-boosted danoprevir in combination with Pegasys [peginterferon alfa-2a] and ribavirin) in prior null responder patients | Drug: RO5024048<br>* 1000 mg orally bid, 24 weeks<br>Drug: danoprevir<br>* 100 mg orally bid, 24 weeks<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg weekly, 24 weeks<br>Drug: ribavirin<br>* 1000-1200 mg/kg/day orally in two divided doses, 24 weeks<br>Drug: ritonavir<br>* 100 mg orally bid, 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of adverse events |  | 48 weeks | 
| Pharmacokinetics (PK): Area under the concentration-time curve (AUC) |  | Intensive PK sample collection during initial 2 week dosing period, followed by routine sampling during treatment up to Week 24 | 
| Antiviral activity: Hepatitis C virus (HCV) RNA levels assessed by Roche COBAS Taqman HCV Test |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emergence of viral resistance: HCV RNA gene sequence variations |  | From baseline to Week 48 | 
| Virologic response: HCV RNA levels |  | approximately 1 year |