Study of INT-747 in Patients With Diabetes and Presumed NAFLD

An Exploratory Study of INT-747 in Patients With Type 2 Diabetes Mellitus and Presumed Nonalcoholic Fatty Liver Disease

The primary objectives of this study are to assess, in patients with Type 2 diabetes mellitus (DM) and presumed nonalcoholic fatty liver disease (NAFLD), the following:

• The safety and tolerability of multiple doses of INT 747;
• The effects of 2 dose levels (25 mg and 50 mg) of INT 747 on insulin resistance and glucose homeostasis;
• Effects of INT-747 on hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function and inflammation, and;
• Trough concentrations of INT-747 and its metabolites, glyco 6-ethyl chenodeoxycholic acid (6-EDCA) and tauro 6-ECDCA.

This is a multi-center, double-blind, randomized, placebo-controlled, multiple-dose, parallel-group study. Three (3) cohorts of 12 patients each will receive either placebo, 25 mg INT-747, or 50 mg INT-747 by mouth daily for 6 weeks.

The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43). Other endpoints will be evaluated by monitoring adverse experiences; vital signs; clinical laboratory values; plasma drug and metabolite concentrations; and general health and well-being.

Inclusion Criteria:

• Type 2 diabetes, defined by the American Diabetes Association (ADA), as one of the following criteria:
• Symptoms of diabetes plus casual plasma glucose concentration >200 mg/dL (11.1 mmol/L) or
• Fasting plasma glucose >126 mg/dL (7.0 mmol/L) or
• 2-hour post-load glucose >200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test (GTT).
• Presumed NAFLD, defined by one of the following criteria:
• Alanine aminotransferase (ALT) ≥47 U/L for females and ≥56 U/L for males
• Aspartate aminotransferase (AST) ≥47 U/L for females and ≥60 U/L for males
• Enlarged liver (demonstrated by ultrasound or other imaging technique)
• Diagnostic histological findings shown on prior biopsy (in the last 5 years).

Exclusion Criteria:

• Bilirubin >2 × ULN
• ALT >155 U/L for females and >185 U/L for males.
• AST >155 U/L for females and >200 U/L for males.
• Patients taking any antidiabetic medications, with the exception of metformin and sulfonylureas. If the HbA1c is <11%, patients may be enrolled who have been withdrawn from all other diabetic medications as specified in the protocol, at the discretion of the Principal Investigator.