Non-Alcoholic Steatohepatitis (NASH) MedDRA version: 9.1 Level: LLT Classification code 10053219 Term: Non-alcoholic steatohepatitis
Conditions
Interventions
Product Name: N/A
Product Code: GS-9450
Pharmaceutical Form: Capsule*
CAS Number: 908253-63-4
Current Sponsor code: GS-9450
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration
Sponsors
Gilead Sciences Incorporated
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. • Male or female • 18 through 75 years of age, inclusive • ALT > 60 U/L at screening • Fatty liver on screening ultrasound • Biopsy-proven NASH diagnosed on liver biopsy that has been performed = 12 months prior to screening. If there is no qualifying legacy biopsy, a liver biopsy must be performed during screening for study entry (all other eligibility criteria must be met prior to procedure) • Subjects with type 2 (non-insulin dependent) diabetes for 4%; see exclusions) for 8 weeks prior to screening and should maintain consistent diet, food intake, and physical exercise during the study. Pre-existing weight reduction programs should be stably managed without change during the study (from screening through the Follow-up Week 4 Visit). Study participants are asked to defer initiation of a new weight reduction program until completion of this study. • Negative serum ß-HCG pregnancy test (for females =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. • Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study. • Males and females of reproductive potential who are not willing to use an effective method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception. • Where required by local law or regulation, the participation of female subjects may be limited to women of non-childbearing potential or, if deemed appropriate, to males only in that country • A > 4% decrease in weight within 8 weeks of screening. • Diagnosis of type 1 (insulin-dependent) diabetes mellitus • Presence of diabetic peripheral neuropathy or gastroparesis or duration of type 2 diabetes = 10 years • Currently receiving sulfonylureas or glitazones (sulfonylureas will be allowed if a forthcoming pharmacology study shows no drug-drug interaction) • Have received glitazones within 6 months prior to screening • Cirrhosis or decompensated liver disease at screening, defined as direct (conjugated) bilirubin > 1.5 × upper limit of the normal range (ULN), prothrombin time > 1.5 × ULN, platelets 50 ng/mL or other standard of care measure • Serological evidence of infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) • Presence of other forms of liver disease (including, but not limited to, alcoholic liver disease; viral or autoimmune hepatitis; a-1-antitrypsin deficiency; hemochromatosis; Wilson’s disease; primary biliary cirrhosis; primary sclerosing cholangitis; prior exposure to organic solvents such as carbon tetrachloride; drug-induced liver disease; or other metabolic, hereditary or infectious liver disease) • History of hemochromatosis or iron overload, as defined by presence of 3 + or 4+ stainable iron on liver biopsy • History of excessive alcohol ingestion, averaging > 30 gm/day (3 drinks/day) in the previous 2 years, or current alcohol intake averaging > 20 gm/day (2 drinks/day) for females and > 30 gm/day (3 drinks/day) for males • History of or current binge drinking • History of acute substance abuse within one year of screening • History of or currently ingesting drugs possibly associated with hepatic steatosis within the past year (amiodarone, diltiazem, tamoxifen, systemic glucocorticoids, anabolic steroids, high-dose estrogens [contraceptives and hormone replacement therapy are allowed], methotrexate, valproic acid, or perhexiline) • History of ingesting drugs that may improve NASH and associated fibrosis (orlistat, sibutramine, and other weight loss drugs, S-adenosyl-L-methionine, betaine, and urosodeoxycholic acid) within 3 months prior to screening • History of ingesting anti-tumor necrosis factor (anti-TNFa) drugs or immunomodulators within 3 months prior to screening • History of total parenteral nutrition within the past 6 months • History of gastroplasty, jejunoileal bypass, or jejunocolonic bypass surgery • Prior or current malignancy of any organ system and skin cancer (previously excised basal cell carcinoma is all
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To investigate the safety and tolerability of multiple oral doses of GS 9450 in subjects with NASH;Secondary Objective: • To investigate the pharmacokinetics of multiple oral doses of GS 9450 and its metabolites in subjects with NASH • To investigate the activity of multiple oral doses of GS 9450 in subjects with NASH, as evidenced by: (1) change from baseline in CK 18 fragments, (2) change from baseline in ALT, and (3) change from baseline in other non-invasive biomarkers (including metabolic markers) ;Primary end point(s): Primary Endpoints Safety Endpoints The primary safety endpoint will evaluate the tolerability of multiple oral doses of GS-9450. This endpoint will be assessed using treatment-limiting adverse events or laboratory abnormalities that require premature discontinuation from the study. Activity Endpoints The primary activity endpoints are the following at Week 4: • Change (absolute, percent) from baseline in CK-18 fragments, ALT, and AST levels; Additionally, change from baseline in non-invasive markers (C-peptide, free fatty acids, adiponectin, IL-6, TNFa, FibroTest, high-sensitivity C- reactive protein) will be evaluated. The following endpoints, which may affect activity, will be evaluated at Week 4: • change in body weight and BMI from baseline; and • change in serum lipid profile from baseline. Pharmacokinetic Endpoints The primary pharmacokinetic endpoints of this study are to characterize the plasma pharmacokinetic parameters of GS-9450 and metabolites following multiple doses of GS-9450. The pharmacokinetic parameter endpoints to be evaluated are Week 2-4 Cmax, Tmax, Cmin, ?z, T1/2, AUCtau, Vdss/F (GS-9450 only) and CL/F (GS-9450 only). | — |
Countries
France
Outcome results
None listed