Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis
Condition: Liver Cirrhosis, Biliary
MeSH terms: Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary; Fibrosis
Intervention: Obeticholic Acid (OCA); Placebo
Intervention description: Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants).
Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study.; One tablet daily (or a lower frequency depending on CP score) for the remainder of the study
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 334.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Primary Biliary Cirrhosis; PBC; Cirrhosis; Liver

Summary:

      Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver
      disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and
      eventual cirrhosis requiring liver transplantation or resulting in death. The investigational
      drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the
      primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including
      its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its
      hepatoprotective effects and result in attenuation of injury and improved liver function in a
      cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to
      placebo, combined with stable standard care, on clinical outcomes in PBC participants.
    

Eligibility criteria:

        Key Inclusion Criteria:

          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

        Exclusion Criteria:

          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)