The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment Trial(FLINT)

The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) Trial

Administration of the farnesoid X receptor (FXR) ligand obeticholic acid (OCA) for 72 weeks to subjects with biopsy evidence of nonalcoholic steatohepatitis (NASH) will result in improvement in their liver disease as measured by changes in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS).

To evaluate whether treatment with obeticholic acid, 25 mg daily for 72 weeks compared to treatment with placebo, improves the severity of nonalcoholic fatty liver disease (NAFLD) as determined from hepatic histology.

Inclusion Criteria:

• 18 years of age or older as of the initial screening interview and provision of consent
• Histologic evidence of definite or probable nonalcoholic steatohepatitis (NASH) based upon a liver biopsy obtained no more than 90 days prior to randomization and a nonalcoholic fatty liver disease activity score (NAS) of 4 or greater with at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).

Exclusion Criteria:

• Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 grams per day in females and more than 30 grams per day in males, on average)

• Inability to reliably quantify alcohol consumption based upon local study physician judgment

• Use of drugs historically associated with nonalcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for more than 2 weeks in the year prior to randomization

• Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass)

• Uncontrolled diabetes defined as Hemoglobin A1c 9.5% or higher within 60 days prior to enrollment

• Presence of cirrhosis on liver biopsy

• A platelet count below 100,000/mm3

• Clinical evidence of hepatic decompensation as defined by the presence of any of the following abnormalities:

  • Serum albumin less than 3.2 grams/deciliter (g/dL)
  • International Normalized Ratio(INR)greater than 1.3
  • Direct bilirubin greater than 1.3 milligrams per deciliter (mg/dL)
  • History of esophageal varices, ascites or hepatic encephalopathy

• Evidence of other forms of chronic liver disease:

  • Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)
  • Hepatitis C as defined by presence of hepatitis C virus (HCV) ribonucleic acid (RNA) or positive hepatitis C antibody (anti-HCV)
  • Evidence of ongoing autoimmune liver disease as defined by compatible liver histology
  • Primary biliary cirrhosis as defined by the presence of at least 2 of these criteria (i) Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation (ii)Presence of anti-mitochondrial antibody (AMA) (iii)Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts
  • Primary sclerosing cholangitis
  • Wilson's disease as defined by ceruloplasmin below the limits of normal and compatible liver histology
  • Alpha-1-antitrypsin(A1AT) deficiency as defined by diagnostic features in liver histology (confirmed by alpha-1 antitrypsin level less than normal; exclusion at the discretion of the study physician)
  • History of hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable iron on liver biopsy
  • Drug-induced liver disease as defined on the basis of typical exposure and history
  • Known bile duct obstruction
  • Suspected or proven liver cancer
  • Any other type of liver disease other than nonalcoholic steatohepatitis (NASH)

• Serum alanine aminotransferase (ALT) greater than 300 units per liter (U/L)

• Serum creatinine of 2.0 mg/dL or greater

• Use of ursodeoxycholic acid (Ursodiol, Urso) within 90 days prior to enrollment

• Inability to safely obtain a liver biopsy

• History of biliary diversion

• Known positivity for Human Immunodeficiency Virus (HIV) infection

• Active, serious medical disease with likely life expectancy less than 5 years

• Active substance abuse including inhaled or injection drugs in the year prior to screening

• Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial, breast feeding

• Participation in an investigational new drug (IND) trial in the 30 days before randomization

• Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study

• Failure to give informed consent