Study of OCA Evaluating Pharmacokinetics and Safety in Patients With PBC and Hepatic Impairment
Study of OCA Evaluating Pharmacokinetics and Safety in Patients With PBC and Hepatic Impairment
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and
 safety of OCA treatment in patients with primary biliary cholangitis (PBC) and moderate to
 severe hepatic impairment over a 48 week treatment period. Patients who have completed their
 48-week double blind treatment period will continue double-blind treatment until all
 randomized patients have completed their 48-week treatment period and the database for that
 period is locked. An open-label extension study in which all patients receive OCA will be
 considered following review of blinded safety and PK data.
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 [Lindor 2009, EASL 2009]), defined as having ≥2 of the
 following 3 diagnostic factors:

 -  History of elevated 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-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 (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 ≥16.9kPa

 -  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/mm3) with

 -  persistent decrease in serum albumin, or

 -  elevation in prothrombin time /INR (not due to antithrombotic agent use), or

 -  elevated bilirubin (2× ULN)

 3. Satisfy the criteria of the modified CP classification for hepatic impairment during
 Screening:

 -  Moderate: CP-B (Scores 7 to 9) or

 -  Severe: CP-C (Scores 10 to 12)

 4. MELD score of 6 to 24 at Screening

 5. Taking 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 [AASLD, EASL 2014])

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

 -  Hepatitis C virus infection and RNA positive

 -  Active hepatitis B infection; however, patients 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