Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC)
Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC)
This is a phase 2, double-blind, placebo controlled trial in patients with primary sclerosing
 cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular,
 serum alkaline phosphatase; and, safety.
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of
 the efficacy and safety of OCA in subjects with PSC. Approximately 75 subjects who provide
 written informed consent and meet all of the inclusion and none of the exclusion criteria
 will be randomized to 1 of 3 treatment groups as follows: 1.5 mg titrating to 3 mg OCA, 5 mg
 titrating to 10 mg OCA, or placebo, in a 1:1:1 ratio. Subjects will administer
 investigational product (IP) orally, once daily for 2 consecutive 12-week periods.

 For the first 12 weeks, the subject's dose will be 1.5 mg OCA, 5 mg OCA, or placebo. After 12
 weeks, the subject's dose will be titrated as follows, providing there are no limiting safety
 or tolerability concerns in the opinion of the investigator, while maintaining the trial
 blind: the 1.5 mg OCA treatment group will titrate to 3 mg, the 5 mg OCA treatment group will
 titrate to 10 mg OCA, and the placebo group will remain on placebo. Double-blind treatment
 will continue for a further 12 weeks at that dose.

 Any subjects whose dose is not titrated, due to safety or tolerability concerns, will remain
 on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the
 double-blind phase to Week 24.

 Randomization will be stratified by the presence or absence of concomitant ursodeoxycholic
 acid (UDCA) use and total bilirubin level (≤ 1.5x upper limit of normal [ULN] or > 1.5x ULN
 but < 2.5x ULN).
Inclusion Criteria:

 -  Male or female aged 18 to 75 years

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

 -  Must have a diagnosis of PSC (based on cholangiography at any point in time)

 -  Alkaline phosphatase (ALP) at Screening ≥ 2x ULN

 -  Total bilirubin at Screening < 2.5x ULN.

 -  For subjects with concomitant inflammatory bowel disease (IBD):

 1. Colonoscopy (if subject has a colon) or other appropriate endoscopic procedure
 within 12 months of Day 0 confirming no dysplasia or colorectal cancer

 2. Subjects with Crohn's Disease (CD) must be in remission as defined by a Crohn's
 Disease Activity Index (CDAI) <150.

 3. Subjects with ulcerative colitis (UC) must either be in remission or have mild
 disease. Remission is defined as a partial Mayo score of ≤2 with no individual
 sub-score exceeding 1. Mild disease is defined as a partial Mayo score ≤3 with no
 individual sub-score exceeding 1 point.

 -  For subjects being administered UDCA as part of their standard of care, the dose must
 have been stable for ≥ 3 months prior to, and including, Day 0 and must not have
 exceeded 20 mg/kg/day during this time.

 -  Subjects being administered biologic treatments (eg, anti-tumor necrosis factor (TNF)
 or anti-integrin monoclonal antibodies), immunosuppressants, systemic corticosteroids,
 or statins, must have been on a stable dose for ≥ 3 months prior to, and including,
 Day 0 and should plan to remain on a stable dose throughout the trial.

 -  Contraception: female subjects of childbearing potential must use ≥ 1 effective method
 (≤1% failure rate) of contraception during the trial and until 4 weeks following the
 last dose of IP (including long term safety extension doses).

 Exclusion Criteria:

 -  Evidence of a secondary cause of sclerosing cholangitis at Screening

 -  Immunoglobulin G4 (IgG4) > 4x ULN at Screening or evidence of IgG4 sclerosing
 cholangitis

 -  Small duct cholangitis in the absence of large duct disease

 -  Presence of clinical complications of chronic liver disease or clinically significant
 hepatic decompensation, including:

 -  Current Child Pugh classification B or C

 -  History of, or current diagnosis or suspicion of, cholangiocarcinoma or other
 hepatobiliary malignancy, or biliary tract dysplasia.

 -  History of liver transplantation, or current model of end stage liver disease score ≥
 12

 -  History of, or current, cirrhosis with complications, including history or presence of
 spontaneous bacterial peritonitis hepatocellular carcinoma or hepatic encephalopathy
 (as assessed by the investigator)

 -  Current known portal hypertension with complications, including known gastric or large
 esophageal varices, poorly controlled or diuretic resistant ascites, history of
 variceal bleeds, or related therapeutic or prophylactic interventions (e.g., beta
 blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt
 [TIPS])

 -  History of, or current, hepatorenal syndrome (type I or II) or Screening serum
 creatinine > 2 mg/dL (178 μmol/L)

 -  Platelet count < 50 x 10⁹/L

 -  Current clinical evidence of dominant strictures that are considered clinically
 relevant in the opinion of the Investigator or current biliary stent at Screening

 -  Current cholecystitis or evidence of current biliary obstruction due to gallstones.
 Asymptomatic gallstones that are not considered a safety risk in the opinion of the
 Investigator might be acceptable subject to discussion and agreement with the Medical
 Monitor.

 -  Colonic dysplasia within ≤ 5 years prior to Day 0

 -  History of small bowel resection

 -  History of other chronic liver diseases, including, but not limited to, primary
 biliary cirrhosis (PBC), alcoholic liver disease, non-alcoholic fatty liver disease
 (NAFLD), autoimmune hepatitis, hepatitis B virus (unless seroconverted and no positive
 Hepatitis B Virus DNA), hepatitis C virus and overlap syndrome

 -  Known Gilbert's syndrome or history of elevations in unconjugated (indirect) bilirubin
 >ULN or unconjugated (indirect) bilirubin >ULN at Screening

 -  Known history of human immunodeficiency virus (HIV) infection

 -  Currently experiencing, or experienced within ≤ 3 months of Screening, pruritus
 requiring systemic or enteral treatment

 -  Known or suspected acute cholangitis in the 3 months prior to, and including, Day 0
 including cholangitis treated with antibiotics

 -  Administration of antibiotics is prohibited ≤1 month of Day 0 (unless subject is on a
 stable prophylaxis dose for at least 3 months prior to Day 0).

 -  Administration of the following medications is prohibited ≤ 6 months of Day 0 and
 throughout the trial: fenofibrate or other fibrates and potentially hepatotoxic
 medications (including α-methyl-dopa, sodium valproic acid, isoniazide, or
 nitrofurantoin).

 -  IBD flare during Screening (up to and including Day 0), where "flare" is defined as
 follows:

 -  UC flare: partial Mayo Score ≥5, and

 -  CD flare: CDAI ≥250

 -  Evidence of deleterious effects of alcohol abuse (as assessed by the investigator) or
 excessive alcohol consumption (>4 units/day for males, >2 units/day for females)

 -  Known or suspected use of illicit drugs or drugs of abuse (allowed if medically
 prescribed or indicated) within 3 months of Day 0

 -  If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a
 positive serum pregnancy test), or lactating

 -  Other concomitant disease, malignancy, or condition likely to significantly decrease
 life expectancy to less than the duration of the trial (e.g., moderate to severe
 congestive heart failure)

 -  Participation in another investigational drug, biologic, or medical device trial
 within 30 days prior to Screening

 -  History of noncompliance with medical regimens, or subjects who are considered to be
 potentially unreliable

 -  Blood or plasma donation within 30 days prior to Day 0

 -  Mental instability or incompetence such that the validity of informed consent or
 compliance with the trial is uncertain.