A Study of Response-Guided Duration of Combination Therapy With GS-9190, GS-9256, Pegasys® and Copegus® in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C

Study Overview
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Brief Summary
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This phase 2b study will evaluate the efficacy and safety of 16 and 24 weeks of response-guided duration of therapy with GS-9190 and GS-9256 in combination with Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®). Additionally, the efficacy and safety of 24 weeks of GS-9256 in combination with Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) will be evaluated.

Official Title
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A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating 16 and 24 Weeks of Response Guided Therapy With GS-9190, GS-9256, Ribavirin (Copegus®) and Peginterferon Alfa 2a (Pegasys®) in Treatment Naïve Subjects With Chronic Genotype 1 Hepatitis C Virus Infection (Protocol No. GS-US-196-0123)

Conditions
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Chronic Hepatitis C Infection

Intervention / Treatment
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* Drug: GS-9190
* Drug: GS-9256
* Biological: Pegasys®
* Drug: Copegus®
* Drug: GS-9190 placebo
* Drug: GS-9256
* Biological: Pegasys®
* Drug: Copegus®
* Drug: GS-9190 placebo
* Drug: GS-9256 placebo
* Biological: Pegasys®
* Drug: Copegus®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects 18 to 70 years of age Chronic HCV infection for at least 6 months prior to Baseline (Day 1) Liver biopsy results (performed no more than 2 years prior to Screening) indicating the absence of cirrhosis Monoinfection with HCV genotype 1a or 1b HCV treatment-naïve Body mass index (BMI) between 18 and 36 kg/m2 Creatinine clearance >/= 50 mL/min Subject agrees to use highly effective contraception methods if female of childbearing potential or sexually active male. Screening laboratory values within defined thresholds for ALT, AST, leukopenia, neutropenia, anemia, thrombocytopenia, thyroid stimulating hormone (TSH), potassium, magnesium Exclusion Criteria: Autoimmune disease Decompensated liver disease or cirrhosis Poorly controlled diabetes mellitus Severe psychiatric illness Severe chronic obstructive pulmonary disease (COPD) Serological evidence of co-infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or another HCV genotype Suspicion of hepatocellular carcinoma or other malignancy (with exception of certain skin cancers) History of hemoglobinopathy Known retinal disease Subjects who are immunosuppressed Subjects with known, current use of amphetamines, cocaine, opiates (i.e., morphine, heroin), methadone, or ongoing alcohol abuse Subjects who are on or are expected to be on a potent cytochrome P450 (CYP) 3A4 or Pgp inhibitor, or a QT prolonging medication within 2 weeks of Baseline (Day 1) or during the study Subjects must have no history of clinically significant cardiac disease, including a family history of Long QT syndrome, and no relevant electrocardiogram (ECG) abnormalities at screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>GS-9190 and GS-9256 in combination with Pegasys® and Copegus® for 16 or 24 weeks; Pegasys® and Copegus® may be continued for up to 48 weeks total duration depending on individual response to therapy | Drug: GS-9190<br>* GS-9190 capsule, 20 mg BID, 16 or 24 weeks<br>Drug: GS-9256<br>* GS-9256 capsule, 150 mg BID, 16 or 24 weeks<br>Biological: Pegasys®<br>* peginterferon alfa-2a, (solution for injection) 180 µg/week, up to 48 weeks<br>Drug: Copegus®<br>* ribavirin 200 mg tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day >/= 75 kg) divided twice daily (BID), up to 48 weeks<br>|
| Experimental: Arm 2<br>GS-9256 (active) and placebo matching GS-9190 in combination with Pegasys® and Copegus® for 24 weeks; Pegasys® and Copegus® may be continued for up to 48 weeks total duration depending on individual response to therapy | Drug: GS-9190 placebo<br>* placebo matching GS-9190 capsule BID, 24 weeks<br>Drug: GS-9256<br>* GS-9256 capsule, 150 mg BID, 24 weeks<br>Biological: Pegasys®<br>* peginterferon alfa-2a (solution for injection) 180 µg/week, up to 48 weeks<br>Drug: Copegus®<br>* ribavirin 200 mg tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day >/= 75 kg) divided twice daily (BID), up to 48 weeks<br>|
| Placebo Comparator: Arm 3<br>Placebo matching GS-9190 and placebo matching GS-9256 in combination with Pegasys® and Copegus® for 24 weeks; Pegasys® and Copegus® will be continued for up to 48 weeks total duration | Drug: GS-9190 placebo<br>* placebo matching GS-9190 capsule BID, 24 weeks<br>Drug: GS-9256 placebo<br>* placebo matching GS-9256 capsule BID, 24 weeks<br>Biological: Pegasys®<br>* peginterferon alfa-2a (solution for injection) 180 µg/week, 48 weeks<br>Drug: Copegus®<br>* ribavirin 200 mg tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day >/= 75 kg) divided twice daily (BID), 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response (SVR) defined as undetectable HCV RNA 24 weeks after treatment cessation |  | 24 weeks of off-treatment follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of therapy as measured by frequency of laboratory abnormalities, reported adverse events, and discontinuations due to adverse events |  | Through up to 48 weeks treatment period and 24 weeks of off-treatment follow-up | 
| Emergence of viral resistance following initiation of therapy with GS-9190 and GS-9256 |  | Through up to 48 weeks treatment period, 24 weeks of off-treatment follow-up, and up to 48 weeks of follow-up in the Resistance Registry Substudy | 
| Viral dynamics and steady state pharmacokinetics of GS-9190 and GS-9256 when administered in combination with PEG and RBV; measured by HCV RNA levels and plasma concentrations of GS-9190 and GS-9256 over time |  | Through Week 4 of therapy | 
| Long-term assessment of plasma HCV RNA in subjects who achieve SVR | Plasma HCV RNA will be measured at approximately 6, 12, 24, and 36 months after Week 72. | 36 months following Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C, HCV, Rapid Virologic Response, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, HCV RNA, Polymerase inhibitor, Protease inhibitor, Treatment naïve, GS-9190, GS-9256