A Study of RO5024048 in Combination With Ritonavir-Boosted Danoprevir With or Without Copegus (Ribavirin) in Interferon-Naïve Patients With Chronic Hepatitis C Genotype 1 (INFORM-SVR)

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, parallel group study will evaluate the safety and efficacy of the combination RO5024048 and ritonavir-boosted danoprevir with and without Copegus (ribavirin) in patients with chronic hepatitis C genotype 1. In arm A and B, interferon treatment-naïve patients will receive 1000 mg RO5024048 orally twice daily and 100 mg danoprevir with 100 mg ritonavir orally twice daily plus either Copegus (1000 mg or 1200 mg orally daily) or placebo for 12 weeks. Depending on viral response and treatment arm patients will be re-randomized to continue assigned treatment for additional 12 weeks or stop all treatment. The anticipated time on study treatment is up to 24 weeks plus a 24-week follow-up. As of 29. September 2011, Arm B patients (placebo-containing arm) will be offered, in conjunction with the current treatment, Pegasys (peginterferon alfa-2a) 180 mcg subcutaneously weekly plus Copegus 1000mg or 1200 mg orally daily for 24 weeks, with a 24-week follow-up.

Official Title
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INFORM-SVR: A Randomized, Multi-Center Study of Interferon-Free Treatment With a Combination of a Polymerase Inhibitor (RO5024048) and a Ritonavir Boosted HCV Protease Inhibitor (RO5190591/r, DNV/r) With or Without Copegus® in Interferon Naïve HCV Genotype 1 Infected Patients

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Copegus placebo
* 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 patient, >/= 18 years of age Chronic Hepatitis C of >/= 6 months duration at screening HCV genotype 1 and quantifiable HCV RNA at screening (Roche COBAS TaqMan HCV test) Naïve for treatment with interferon (pegylated or non-pegylated) Body Mass Index (BMI) 18-35 inclusive, minimum weight 45 kg Females of child-bearing potential and males with female partners of childbearing potential must use 2 forms of effective non-hormonal contraception Exclusion Criteria: Pregnant or lactating women and males with female partners who are pregnant or lactating Decompensated liver disease or impaired liver function Cirrhosis or incomplete/transition to cirrhosis Non-hepatitis C chronic liver disease Hepatitis B or HIV infection History of neoplastic disease within the last 5 years, except for localized or in situ carcinoma of the skin History of pre-existing renal disease (except for nephrolithiasis) or severe cardiac disease History of drug or alcohol abuse within the last year or alcohol consumption of > 2 units per day; cannabinoid use is excepted

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm B Extension<br>All patients in treatment arm B were offered to receive Pegasys/Cogepus therapy for an additional 24 weeks. | Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg sc weekly, 24 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg daily orally in split doses (morning/evening), up to 24 weeks<br>|
| Experimental: RO5024048 & ritonavir-boosted danoprevir without Ribavirin (B)<br> | Drug: Copegus placebo<br>* 1000 mg or 1200 mg daily orally in split doses (morning/evening), up to 24 weeks<br>Drug: RO5024048<br>* 1000 mg bid orally, up to 24 weeks<br>Drug: danoprevir<br>* 100 mg bid orally, up to 24 weeks<br>Drug: ritonavir<br>* 100 mg bid orally, up to 24 weeks<br>|
| Experimental: RO5024048 and ritonavir-boosted danoprevir with Ribavirin (A)<br> | Drug: RO5024048<br>* 1000 mg bid orally, up to 24 weeks<br>Drug: danoprevir<br>* 100 mg bid orally, up to 24 weeks<br>Drug: ribavirin [Copegus]<br>* 1000 mg or 1200 mg daily orally in split doses (morning/evening), up to 24 weeks<br>Drug: ritonavir<br>* 100 mg bid orally, up to 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virological response, defined as undetectable HVC RNA measured by Roche COBAS TaqMan HCV test |  | 24 weeks after end of treatment | 
| Safety: Incidence of adverse events |  | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological response (HCV RNA measured by Roche COBAS Taqman HCV test) |  | up to 48 weeks | 
| Impact of Copegus (ribavirin) on efficacy of the direct-acting antiviral combination regimen: viral response (HCV RNA measured by Roche COBAS TaqMan HCV test) |  | 1.5 years | 
| Comparison of 12 and 24 weeks of treatment duration: viral response (HCV RNA measured by Roche COBAS TaqMan HCV test) |  | 1.5 years | 
| Pharmacokinetics: Plasma concentrations of danoprevir, ritonavir, RO4995855 (parent drug of RO5024048) and ribavirin |  | up to 24 weeks | 
| Viral resistance: HCV RNA sequencing and phenotypic analyses |  | up to 48 weeks | 
| Effect of interleukin 28B genotype on efficacy: viral response (HCV RNA measured by Roche COBAS TaqMan HCV test) |  | 1.5 years | 
| Quality of life: SF-36 questionnaire, Fatigue Severity Scale |  | up to 36 weeks |