Use of a Novel Drug in People With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)

We propose to combine voxel matched magnetic resonance spectroscopy (MRS) and magnetic
resonance elastography (MRE) liver (pre vs. post) to evaluate hepatic fat and hepatic
fibrosis. We will also establish glucose tolerance status by our established labeled oral
glucose tolerance test (OGTT) (6,6 ²H2 glucose). Following baseline evaluation subjects with
biopsy/MRE proven NASH will be randomized to one of two groups and treated either with active
drug (AZ compound) or placebo for 12 weeks (plus or minus 1 week). Subjects with history
suggestive of non-alcoholic fatty liver disease (NAFLD) or NASH will be invited to
participate. If they meet criteria following initial screening they will be included in the
study. OGTT, liver MRS, MRE will be repeated. Liver enzymes [aspartate aminotransferase
(AST), alanine aminotransferase (ALT),alkaline phosphatase (ALP)] as well as other safety
tests [creatine phosphokinase (CPK), thyroid stimulating hormone (TSH), international
normalized ratio (INR),total bilirubin] will be measured before, monthly during therapy and
at one month following therapy.

Inclusion Criteria:

- Age: 21-75

- Body Mass Index (BMI) >19 kg/m^2

- Subjects with biopsy/MRE proven NASH [MRS liver fat ≥ 5%, with elevated liver enzymes
ALT <5x upper limit normal (ULN)].

- Subjects with NAFLD and MRE shows F1 or greater fibrosis

- Subjects with history suggestive of NAFLD/NASH

- Total bilirubin must be < 1.5 x ULN and INR must be < 1.3 at baseline screening.

- TSH and CPK will be within normal limits (WNL) at screening.

- Subjects with type 2 diabetes who are on stable doses of medications (except
pioglitazone) to control hyperglycemia and have baseline HbA1c of 10% or lower.

- Hemoglobin must be greater than or equal to 12.0 in males and 11.0 in females.

Exclusion Criteria:

- Medications that may affect glucose metabolism such as corticosteroids, opiates,
barbiturates, and anticoagulants.

- Subjects with anemia, and symptoms suggestive of undiagnosed illness, overt hepatic
disease, stroke, Alzheimer's disease, autoimmune hepatitis, alcoholism or increased
alcohol consumption over the American Diabetes Association (ADA) guidelines.

- Any disorder that may potentially impact the outcome measures.

- Pregnant women and children.

- Subjects planning weight loss or in any weight loss program.

- Subjects taking TZD's, Atazanavir, Indinavir, Ketoconazole, Valproic acid, Silybum
marianum and Valeriana officinalis.