A Phase 2, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Activity of GS 9450 in Adults With Non-Alcoholic Steatohepatitis (NASH)
Overview
- Phase
- Phase 2
- Intervention
- GS-9450
- Conditions
- Nonalcoholic Steatohepatitis
- Sponsor
- Gilead Sciences
- Enrollment
- 124
- Primary Endpoint
- Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
The overall purpose of this study is to examine the safety, tolerability, pharmacokinetics (how the body processes a drug), and activity of GS-9450 in preventing liver damage due to scarring, or fibrosis, caused by Non-Alcoholic Steatohepatitis (also known as NASH).
Detailed Description
This is a Phase 2, randomized, double-blind, parallel group, placebo controlled, multicenter study investigating the safety, tolerability, pharmacokinetics and activity of multiple oral doses of GS 9450 in adults with NASH. Approximately 110 subjects 18 75 years of age with elevated ALT (\> 60 U/L at screening), fatty liver on screening ultrasound, and biopsy-proven NASH will be randomized (1:1:1:1:1) to one of five parallel treatment groups (22 subjects per treatment group) as follows: GS-9450 1mg by mouth (PO) once daily, GS-9450 5 mg PO once daily, GS-9450 10 mg PO once daily, GS-9450 40 mg PO once daily, or Matching placebo PO once daily Qualifying subjects will be stratified by the presence/absence of type 2 diabetes (i.e., on/off oral diabetic medication at entry) and by geographic region (US and France). Following randomization, subjects will return within five business days later for a baseline visit, at which time they will be dispensed study medication and enter a 4-week treatment phase. Upon completion of the treatment phase, subjects will enter a 4 week off-treatment follow-up period. Each subject's participation in the study will last up to approximately 12 weeks (inclusive of screening, treatment phase, and off-treatment follow-up period).
Investigators
Eligibility Criteria
Inclusion Criteria
- •18-75 years of age
- •ALT \> 60 U/L
- •fatty liver on screening ultrasound
- •and biopsy-confirmed NASH
- •platelet count \>/= 75,000/mm3 and adequate hematologic function (absolute neutrophil count \>/= 1,500/mm3, hemoglobin \>/= 11.0 g/dL)
- •calculated creatinine clearance \>/= 70 mL/min
- •non-insulin dependent diabetes for \< 10 years is allowed if stably managed for at least 6 months prior to screening
- •stable weight (no weight loss \> 4%) for 8 weeks prior to screening and should maintain consistent diet, food intake, and physical exercise during the study
- •must have been on stable therapy for at least 3 months prior to screening if receiving 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, niacin, fibrates, vitamin E or angiotensin receptor blockers
- •must have been on a stable treatment regimen for at least 3 months prior to screening if receiving other drugs possibly associated with hepatic adverse events (e.g., isoniazid, itraconazole, ketoconazole, rifabutin, rifampin, and other agents with significant hepatotoxic potential)
Exclusion Criteria
- •Insulin dependent diabetes mellitus, treatment with sulfonylureas (may be allowed pending results from a drug-drug interaction study), subjects receiving glitazones at screening or within 6 months of screening, presence of diabetic peripheral neuropathy or gastroparesis
- •A \> 4% decrease in weight within 8 weeks of screening
- •cirrhosis or decompensated liver disease (defined as conjugated bilirubin \> 1.5 x the upper limit of the normal range (ULN), prothrombin time \> 1.5 x ULN, serum albumin \< 3.0 g/dL, or prior history of clinical hepatic decompensation
- •presence of other form of liver disease other than NASH
- •history of excess alcohol ingestion, averaging \> 3 drinks/day in the previous 2 years; or current alcohol intake averaging \> 2 drinks/day for females and \> 3 drinks per day for males; history of or current binge drinking
- •serological evidence of co-infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV
- •evidence of hepatocellular carcinoma (i.e., α-fetoprotein \> 50 ng/mL)
- •history of ingesting drugs possibly associated with hepatic steatosis within the past year
- •history of total parenteral nutrition within the past 6 months
- •prior history of gastroplasty, jejunoileal, or jejunocolonic bypass surgery
Arms & Interventions
Cohort 1
22 subjects to receive 1 mg GS-9450 for 4 weeks
Intervention: GS-9450
Cohort 2
22 subjects to receive 5 mg GS-9450 for 4 weeks
Intervention: GS-9450
Cohort 3
22 subjects to receive 10 mg GS-9450 for 4 weeks
Intervention: GS-9450
Cohort 4
22 subjects to receive 40 mg GS-9450 for 4 weeks
Intervention: GS-9450
Cohort 5
22 subjects to receive placebo to match GS-9450 for 4 weeks
Intervention: GS-9450 Placebo
Outcomes
Primary Outcomes
Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities
Time Frame: Baseline to Post-treatment Week 24
Secondary Outcomes
- Pharmacokinetics of GS-9450 and its metabolites(Weeks 2 and 4)
- Change from baseline in alanine aminotransferase (ALT)(Baseline to Week 4)