HCV Infection
Conditions
Keywords
apoptosis, liver inflammation, hepatitis C
Brief summary
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.
Interventions
DRUGGS-9450
Taken as one capsule by mouth once daily
DRUGPlacebo
Taken as one placebo capsule (matching in appearance to GS-9450 capsules) by mouth once daily
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 (absolute, percent) from baseline in the Knodell necroinflammatory score | Baseline to Week 24 | — |
| Change from baseline in the percent of apoptotic cells | Baseline to Week 24 | 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 |
| Change from baseline in percent of anti-M30 monoclonal antibody-positive hepatocytes | Baseline to Week 24 | 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 |
| Change From Baseline in HCV RNA | Baseline to to Week 24 | — |
| Change from baseline in hepatic collagen staining area as measured by morphometry of liver biopsy specimens | Baseline to Week 24 | — |
Countries
Canada, Germany, Poland, Puerto Rico, United Kingdom, United States
Outcome results
None listed