Phase 3 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cirrhosis

Open to people ages 18 years and up

1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:
   • History of elevated Alkaline phosphatase levels for at least 6 months
   • Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
   • Liver biopsy consistent with PBC
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN
3. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0

1. History or presence of other concomitant liver diseases including:
   • Hepatitis C virus infection
   • Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
   • Primary sclerosing cholangitis (PSC)
   • Alcoholic liver disease
   • Definite autoimmune liver disease or overlap hepatitis
   • Nonalcoholic steatohepatitis (NASH)
   • Gilbert's Syndrome
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
   • History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
   • Cirrhosis with complications, including history (within the past 12 months) or presence of:
     • Variceal bleed
     • Uncontrolled ascites
     • Encephalopathy
     • Spontaneous bacterial peritonitis
   • Known or suspected HCC
   • Prior transjugular intrahepatic portosystemic shunt procedure
   • Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine >2 mg/dL (178 μmol/L)
3. Mean total bilirubin >5x ULN
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
5. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions)
6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
7. Known history of human immunodeficiency virus infection
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months)

9. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study

   10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 11. Participation in another investigational product, biologic, or medical device study

   within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study

   12. Mental instability or incompetence, such that the validity of informed consent or

   ability to be compliant with the study is uncertain

   13. History of known or suspected clinically significant hypersensitivity to OCA or any of

   its components

   14. UDCA naïve (unless contraindicated)