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

Inclusion Criteria:

1. Definite or probable PBC diagnosis (consistent with American Association for the Studyof Liver Disease [AASLD] and European Association for Study of the Liver [EASL]Practice Guidelines; [Lindor 2009; EASL 2009]), as demonstrated by the presence of ≥ 2of the following 3 diagnostic factors:

• History of elevated alkaline phosphatase (ALP) levels for at least 6 months
• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in lowtiter (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/orantibodies against the major M2 components (pyruvate dehydrogenase complex-E2 [PDC-E2], 2-oxo-glutaric acid dehydrogenase complex)
• Liver biopsy consistent with PBC

2. At least 1 of the following qualifying biochemistry values:

• ALP ≥ 1.67x upper limit of normal (ULN)
• Total bilirubin > ULN but < 2x ULN

3. Age ≥ 18 years
4. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months)prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0.
5. Contraception: Female participants must be postmenopausal, surgically sterile, or ifpremenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method ofcontraception during the trial and for 30 days after the end of treatment (EOT) visit.Effective methods of contraception are considered to be:

• Hormonal (for example, contraceptive pill, patch, intramuscular implant orinjection); or
• Double barrier method, that is, (a) condom (male or female) or (b) diaphragm,with spermicide; or
• Intrauterine device (IUD); or
• Vasectomy (partner); or
• Sexual abstinence

6. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

1. History or presence of other concomitant liver diseases including:

• Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV)infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen [Hbs Ag] and hepatitis B e antigen [Hbe Ag]negative) may be included 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 (due to interpretability of bilirubin levels)

2. Presence of clinical complications of PBC or clinically significant hepaticdecompensation, including:

• History of liver transplantation, current placement on a liver transplant list orcurrent Model for End Stage Liver Disease (MELD) score ≥ 15
• Portal hypertension with complications, including: known gastric or largeesophageal varices, poorly controlled or diuretic resistant ascites, history ofvariceal bleeds or related therapeutic or prophylactic interventions (forexample, beta blockers, insertion of variceal bands or transjugular intrahepaticportosystemic shunt [TIPS]), or hepatic encephalopathy
• Cirrhosis with complications, including history or presence of: spontaneousbacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN
• Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2mg/deciliter dL) (178 micromole [µmol])/liter [L])

3. Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants [BAS] or rifampicin) within 2 months of Day 0 will be excluded
4. Administration of the following medications is prohibited as specified below:

• Prohibited 6 months prior to Day 0 and throughout the trial (that is, to lastdose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate,mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonideand other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
• Prohibited 12 months prior to Day 0 and throughout the trial (that is, to lastdose and/or EOT): antibodies or immunotherapy directed against interleukins orother cytokines or chemokines

5. Participants who have previously participated in a clinical trial of OCA will not beallowed to participate
6. History or presence of clinically concerning cardiac arrhythmias likely to affectsurvival during the trial, or prolongation of Screening (pretreatment) QT or QTcinterval of > 500 milliseconds (msec)
7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by apositive serum pregnancy test), or lactating
8. Known history of human immunodeficiency virus (HIV) infection
9. Presence of any other disease or condition that is interfering with the absorption,distribution, metabolism, or excretion of drugs including bile salt metabolism in theintestine. Participants with inflammatory bowel disease or who have undergone gastricbypass procedures will be excluded (gastric lap band is acceptable).
10. Medical conditions that may cause nonhepatic increases in ALP (for example, Paget'sdisease) or which may diminish life expectancy to < 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such aschronic lymphatic leukemia)
11. Other clinically significant medical conditions that are not well controlled or forwhich medication needs are anticipated to change during the trial
12. Anticipated changes to current concomitant medications during the course of the trial
13. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol perweek (that is, the equivalent of fourteen 4-ounce (125 mL) glasses of wine or fourteen 12 ounce cans/bottles of beer), or other substance abuse within 1 year prior to Day 0
14. Participation in another investigational drug, biologic, or medical device trialwithin 30 days prior to Screening
15. History of noncompliance with medical regimens, or participants who are considered tobe potentially unreliable
16. Blood or plasma donation within 30 days prior to Day 0
17. Mental instability or incompetence, such that the validity of informed consent orcompliance with the trial is uncertain