Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment
Condition: Liver Cirrhosis, Biliary
MeSH terms: Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary; Fibrosis
Intervention: Obeticholic Acid (OCA); Placebo
Intervention description: OCA will be administered per dose and schedule specified in the arm description.; OCA matching placebo will be administered per the schedule specified in the arm description.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Primary Biliary Cholangitis; Primary Biliary Cirrhosis; PBC; Hepatic Impairment; Cirrhosis; Liver

Summary:

      This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the
      pharmacokinetics (PK) and safety of OCA treatment in participants with PBC and moderate to
      severe hepatic impairment over a 48-week treatment period. Participants who have completed
      their 48-week double blind treatment period will continue double-blind treatment until all
      randomized participants have completed their 48-week treatment period and the database for
      that period is locked. An open-label extension study in which all participants receive OCA
      will be considered following review of blinded safety and PK data.
    

Eligibility criteria:

        Inclusion Criteria:

          1. A definite or probable diagnosis of PBC (consistent with American Association for the
             Study of Liver Diseases [AASLD] and European Association for the Study of the Liver
             [EASL] Practice Guidelines, defined as having ≥2 of the following 3 diagnostic
             factors:

               -  History of elevated alkaline phosphatase (ALP) levels for at least 6 months

               -  Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer
                  (≤1:80), PBC specific antibodies (anti-glycoprotein 210 [GP210] and/or
                  anti-SP100) and/or antibodies against the major M2 components (E2 component of
                  mitochondrial pyruvate dehydrogenase complex [PDC-E2], 2-oxo-glutaric acid
                  dehydrogenase complex)

               -  Liver biopsy consistent with PBC (collected at any time prior to Screening)

          2. Evidence of cirrhosis including at least one of the following:

               -  Biopsy results consistent with PBC Stage 4

               -  Liver stiffness as assessed by Transient Elastography (TE) Median Value ≥16.9
                  kilopascals (kPa)

               -  Clinical evidence in the absence of acute liver failure consistent with cirrhosis
                  including: gastroesophageal varices, ascites, radiological evidence of cirrhosis
                  (nodular liver or enlargement of portal vein and splenomegaly)

               -  Combined low platelet count (<140,000/cubic millimeter [mm^3]) with

                    -  persistent decrease in serum albumin, or

                    -  elevation in prothrombin time/international normalized ratio (INR) (not due
                       to antithrombotic agent use), or

                    -  elevated bilirubin (2*upper limit of normal [ULN])

          3. Satisfy the criteria of the modified Child-Pugh (CP) classification for hepatic
             impairment during Screening:

               -  Moderate: CP-B (Scores 7 to 9) or

               -  Severe: CP-C (Scores 10 to 12)

          4. Model of end-stage liver disease (MELD) score of 6 to 24 at Screening

          5. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥3 months)
             prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months)

        Exclusion Criteria:

          1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6)

          2. History of liver transplant or organ transplant

          3. History of alcohol or drug abuse within 12 months prior to Screening

          4. Hepatic encephalopathy (as defined by a West Haven score of ≥2

          5. History or presence of other concomitant liver diseases including:

               -  Hepatitis C virus infection and ribonucleic acid (RNA) positive

               -  Active hepatitis B infection; however, participants 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

               -  Alcoholic liver disease

               -  Definite autoimmune liver disease or overlap hepatitis

               -  Gilbert's Syndrome

          6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic
             function prior to randomization

        Other inclusion/exclusion criteria may apply.