Safety, Tolerability, Pharmacokinetics and Activity of GS-9450 in Adults With Non-Alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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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
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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).

Official Title
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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)

Conditions
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Nonalcoholic Steatohepatitis

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


Participation Criteria
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Eligibility Criteria
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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 history of ingesting drugs within the past 3 months that may improve NASH and associated fibrosis significant gastrointestinal disease that would interfere with absorption of oral medications; inflammatory bowel disease major surgery within the past year clinically significant abnormalities on ECG or other ECG findings that the investigator considers a safety risk significant systemic or major illnesses other than liver disease that, in the opinion of the investigator, would preclude treatment and adequate follow up prior or current malignancy involving any organ system and skin cancer (previously excised basal cell carcinoma allowed) acute ongoing infection, or symptoms of infection pregnant or breastfeeding females acute substance abuse within the past year. history of ingesting anti-TNFα drugs or immunomodulators within the past 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Cohort 1<br>22 subjects to receive 1 mg GS-9450 for 4 weeks | Drug: GS-9450<br>* GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily<br>|
| Experimental: Cohort 2<br>22 subjects to receive 5 mg GS-9450 for 4 weeks | Drug: GS-9450<br>* GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily<br>|
| Experimental: Cohort 3<br>22 subjects to receive 10 mg GS-9450 for 4 weeks | Drug: GS-9450<br>* GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily<br>|
| Experimental: Cohort 4<br>22 subjects to receive 40 mg GS-9450 for 4 weeks | Drug: GS-9450<br>* GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily<br>|
| Placebo Comparator: Cohort 5<br>22 subjects to receive placebo to match GS-9450 for 4 weeks | Drug: GS-9450 Placebo<br>* Placebo to match GS-9450 administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities |  | Baseline to Post-treatment Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of GS-9450 and its metabolites | Pharmacokinetics (Cmax, Tmax, Cmin, λz, t1/2, AUCtau, Vdss/F, and CL/F) measured by plasma sampling | Weeks 2 and 4 | 
| Change from baseline in alanine aminotransferase (ALT) |  | Baseline to Week 4 |