A Study of Danoprevir/Ritonavir and Copegus With RO5024048 and/or Pegasys in Patients With Chronic Hepatitis C

Study Overview
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Brief Summary
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This randomized, open-label, multi-center study will evaluate the sustained virological response, pharmacokinetics and safety of various combinations of danoprevir/ritonavir with Copegus plus RO5024048 and/or Pegasys in patients with chronic hepatitis C infection. Patients will be divided into 2 separate cohorts. Cohort A, previous partial responders, will be randomized to Groups 1-3 and cohort B, previous null responders, will be randomized to Groups 4-6. Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. In addition, Groups 1 and 4 will receive RO5024048 1000 mg twice a day and Copegus 1000 mg or 1200 mg twice a day for 24 weeks; Group 2 will receive Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks; Groups 3, 5 and 6 will receive RO5024048 1000 mg twice a day, Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. In addition, patients in Group 6 will receive another 24 weeks of Pegasys plus Copegus treatment.

Official Title
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A Randomized Open-label Study to Evaluate the Sustained Virologic Response of Danoprevir/Ritonavir and Copegus in Combination With RO5024048 and/or Pegasys in Chronic Hepatitis C Genotype 1 Patients Who Failed Previous Standard Therapy

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Copegus
* Drug: Copegus
* Drug: Pegasys
* Drug: Pegasys
* Drug: RO5024048
* Drug: danoprevir
* Drug: ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, age 18 years and older Presence of hepatitis C infection, genotype 1a or 1b Documentation of previous treatment failure after receiving approved doses of peginterferon plus ribavirin for at least 12 weeks Patients must have discontinued prior hepatitis C treatment at least 12 weeks prior to study start Exclusion Criteria: Infection with any hepatitis C genotype or subtype other than genotype 1a or 1b Patients with cirrhosis Patients who were discontinued from previous peginterferon plus ribavirin therapy due to reasons other than insufficient therapeutic response Co-infection with hepatitis B or human immunodeficiency virus (HIV) History or evidence of chronic liver disease other than hepatitis C

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Previous null responders (Cohort B): Group 4<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. In addition, Group 4 will receive RO5024048 1000 mg twice a day and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 24 weeks<br>Drug: RO5024048<br>* 1000 mg oral doses twice a day for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|
| Experimental: Previous null responders (Cohort B): Group 5<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. Group 5 will receive RO5024048 1000 mg twice a day, Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 24 weeks<br>Drug: Pegasys<br>* 180 microgram subcutaneously once weekly for 24 weeks<br>Drug: RO5024048<br>* 1000 mg oral doses twice a day for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|
| Experimental: Previous null responders (Cohort B): Group 6<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. Group 6 will receive RO5024048 1000 mg twice a day, Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. In addition, patients in Group 6 will receive another 24 weeks of Pegasys plus Copegus treatment. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 48 weeks<br>Drug: Pegasys<br>* 180 microgram subcutaneously once weekly for 48 weeks<br>Drug: RO5024048<br>* 1000 mg oral doses twice a day for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|
| Experimental: Previous partial responders (Cohort A): Group 1<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. In addition, Group 1 will receive RO5024048 1000 mg twice a day and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 24 weeks<br>Drug: RO5024048<br>* 1000 mg oral doses twice a day for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|
| Experimental: Previous partial responders (Cohort A): Group 2<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. In addition, Group 2 will receive Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 24 weeks<br>Drug: Pegasys<br>* 180 microgram subcutaneously once weekly for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|
| Experimental: Previous partial responders (Cohort A): Group 3<br>Patients in all groups will receive danoprevir 100 mg twice a day and ritonavir 100 mg twice a day for 24 weeks. Group 3 will receive RO5024048 1000 mg twice a day, Pegasys 180 microgram subcutaneously once weekly and Copegus 1000 mg or 1200 mg twice a day for 24 weeks. | Drug: Copegus<br>* 1000 mg or 1200 mg daily oral doses for 24 weeks<br>Drug: Pegasys<br>* 180 microgram subcutaneously once weekly for 24 weeks<br>Drug: RO5024048<br>* 1000 mg oral doses twice a day for 24 weeks<br>Drug: danoprevir<br>* 100 mg oral doses twice a day for 24 weeks<br>Drug: ritonavir<br>* 100 mg oral doses twice a day for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virological response (SVR) of danoprevir/ritonavir with RO5024048 and Copegus in patients with previous partial or null response to peginterferon/ribavirin treatment |  | 24 weeks | 
| Sustained virological response (SVR) of danoprevir/ritonavir with Pegasys and Copegus in patients with previous partial response to peginterferon/ribavirin treatment |  | 24 weeks | 
| Sustained virological response (SVR) of danoprevir/ritonavir and RO5024048 with Pegasys and Copegus in patients with previous partial or null response to peginterferon/ribavirin treatment |  | 24 weeks | 
| Sustained virological response (SVR) of danoprevir/ritonavir and RO5024048 with Pegasys and Copegus followed by 24 weeks of Pegasys and Copegus treatment in patients with previous null response to peginterferon/ribavirin treatment |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Incidence of adverse events) of danoprevir, RO5024048 and Copegus |  | 48 weeks | 
| Safety (Incidence of adverse events) of danoprevir, Pegasys and Copegus |  | 48 weeks | 
| Safety (Incidence of adverse events) of danoprevir, RO5024048, Pegasys and Copegus |  | 72 weeks | 
| Virological response over time |  | 48 weeks | 
| Change in danoprevir plasma concentration |  | 24 weeks | 
| Change in RO5024048 plasma concentration |  | 24 weeks | 
| Hepatitis C virus drug resistance profile |  | 24 weeks |