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

A Randomized, Double-Blinded, Placebo-controlled Phase IIa Study to Assess the Efficacy and Safety of a Novel AstraZeneca Compound in Subjects With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)

Does the novel drug decrease liver fat in subjects with NASH or NAFLD as compared to placebo

We propose to evaluate hepatic fat and hepatic fibrosis using magnetic resonance elastography (MRE) liver (pre vs. post). 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 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. Furthermore, we will also do the subgroup analysis in NASH/NAFLD subjects with and without diabetes to see the effect of the drug.

Inclusion Criteria:

• Age: 21-75
• Body Mass Index (BMI) >19 kg/m^2
• Subjects with biopsy/MRE proven NASH [MRE liver fat ≥ 5%, with elevated liver enzymes ALT <5x upper limit normal (ULN)].
• Subjects with NAFLD and MRE shows F0 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.