Efficacy and Safety Study of GS-9450 Treatment for 6 Months in Patients With Chronic Hepatitis C Virus Infection

Study Overview
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Brief Summary
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This is a Phase 2b, randomized, double-blind, parallel-group, placebo-controlled, multicenter study investigating the safety, tolerability and efficacy of two oral doses of GS-9450 in adults with chronic Hepatitis C Virus (HCV). Approximately 240 subjects 18-65 years of age who meet study entry criteria will be randomized (in other words, selected at random, like flipping a coin) to one of three treatment groups (80 subjects per treatment group) as follows:GS-9450 10 mg once daily,GS-9450 40 mg once daily, or matching placebo once daily. Following randomization, subjects will return within seven business days for a Baseline (Day 1) visit, at which time study medication will be dispensed and subjects will enter a 26 week treatment phase. During the treatment phase, subjects will receive study drug once daily for 24 weeks and then taper off of study drug over the following 2 weeks by receiving study drug once every other day for one week and then every 3 days for one week. Following completion of the treatment phase, subjects will enter a 4-week off-treatment follow-up phase.

Official Title
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A Phase 2b, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of GS 9450 in Adults With Chronic Hepatitis C Virus Infection (GS-US-227-0106)

Conditions
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HCV Infection

Intervention / Treatment
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* Drug: GS-9450
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects, ages 18-65 Chronic HCV infection, defined as having documented HCV infection (antibody or RNA positivity) at least 6 months prior to Baseline (Day 1) with HCV viremia at screening Screening Knodell necroinflammatory score >= 3 based on liver biopsy evaluation (as determined by local pathologist) conducted anytime during the 45-day screening period ALT > the upper limit of the normal range (ULN) but < 10 X ULN at the screening visit Previously failed pegylated interferon-based HCV therapy in combination with ribavirin therapy, or is unable to tolerate or has contraindications to receiving interferon or ribavirin therapy BMI between 19 and 36 kg/m2 (inclusive) Creatinine clearance >= 70 mL/min absolute neutrophil count >= 1000/mm3 Hemoglobin > 10 g/dL Have no clinical or laboratory evidence of hepatic decompensation Exclusion Criteria: Decompensated liver disease Child-Pugh grade B or C cirrhosis Evidence of hepatocellular carcinoma Positive urine drug screen for cocaine or amphetamines Infection with HCV genotype 3 Co-infection with hepatitis B virus or human immunodeficiency virus Pancreatitis Recent significant infection or symptoms of infection Autoimmune disorders Any history of seizure Is a public transportation operator (pilot of airplane or ship; air traffic controller; bus, train or subway driver) or operates heavy construction machinery Transplantation History of malignancy Current excessive alcohol ingestion, averaging > 3 drinks/day for females and > 4 drinks/day for males History of or current binge drinking

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-9450 10 mg/day<br>GS-9450 taken as one 10 mg capsule by mouth once daily | Drug: GS-9450<br>* Taken as one capsule by mouth once daily<br>|
| Experimental: GS-9450 40 mg/day<br>GS-9450 taken as one 40 mg capsule by mouth once daily | Drug: GS-9450<br>* Taken as one capsule by mouth once daily<br>|
| Placebo Comparator: Placebo<br>Placebo taken as one placebo capsule by mouth once daily | Drug: Placebo<br>* Taken as one placebo capsule (matching in appearance to GS-9450 capsules) by mouth once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histologic response, defined as a >= 2-point decrease in Knodell necroinflammatory score with no concurrent worsening in the Knodell fibrosis score, at Week 24 . |  | Week 24 on-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change (absolute, percent) from baseline in the Knodell necroinflammatory score |  | Baseline to Week 24 | 
| Change (absolute, percent) from pretreatment in alanine aminotransferase (ALT) levels |  | Baseline to Week 24 | 
| Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities |  | Up to 24 weeks plus 30 days following the last dose of study drug | 
| Change (absolute, percent) from baseline in cytokeratin-18 caspase cleavage fragment levels |  | Baseline to Week 24 | 
| Change from baseline in hepatic collagen staining area as measured by morphometry of liver biopsy specimens |  | Baseline to Week 24 | 
| Change from baseline in the percent of apoptotic cells | Change from baseline in the percent of apoptotic cells (transferase deoxyuridine triphosphate [dUTP] nick end labeling [TUNEL] positive) as measured by TUNEL staining of liver biopsy specimens | Baseline to Week 24 | 
| Change from baseline in percent of anti-M30 monoclonal antibody-positive hepatocytes | Change from baseline in percent of anti-M30 monoclonal antibody-positive hepatocytes (for cytokeratin-18 neoantigen expression) as measured by immunohistochemical staining of liver biopsy specimens | Baseline to Week 24 | 
| Change From Baseline in HCV RNA |  | Baseline to to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apoptosis, liver inflammation, hepatitis C