Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC)

This was a phase 2, double-blind (DB), placebo-controlled trial in participants with primary sclerosing cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular, serum alkaline phosphatase; and, safety. The long-term safety extension (LTSE) phase was conducted to evaluate the safety, tolerability, and efficacy of long-term, open-label use of OCA in participants with PSC who had completed the DB phase of the study.

This was a phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the efficacy and safety of OCA in participants with PSC. Approximately 75 participants who provided written informed consent and met all of the inclusion and none of the exclusion criteria were randomized to 1 of 3 treatment groups as follows: 1.5 milligrams (mg) titrating to 3 mg OCA, 5 mg titrating to 10 mg OCA, or placebo, in a 1:1:1 ratio. Participants self-administered investigational product (IP) orally, once daily for 2 consecutive 12-week periods.

For the first 12 weeks, the participant's dose was 1.5 mg OCA, 5 mg OCA, or placebo. After 12 weeks, the participant's dose was titrated as follows, providing there were no limiting safety or tolerability concerns in the opinion of the Investigator, while maintaining the trial blind: the 1.5 mg OCA treatment group titrated to 3 mg, the 5 mg OCA treatment group titrated to 10 mg OCA, and the placebo group remained on placebo. Double-blind treatment continued for a further 12 weeks at that dose.

Any participant whose dose was not titrated, due to safety or tolerability concerns, remained on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the DB phase to Week 24.

Randomization was 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).

Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the open-label LTSE phase (planned as a further 24 months).

Eligibility Criteria:
Inclusion Criteria:

* Must have had a diagnosis of PSC (based on cholangiography at any point in time).
* Alkaline phosphatase at Screening ≥2x ULN.
* Total bilirubin at Screening \<2.5x ULN.
* For participants with concomitant inflammatory bowel disease (IBD):

  1. Colonoscopy (if participant has a colon) or other appropriate endoscopic procedure within 12 months of Day 0 confirming no dysplasia or colorectal cancer
  2. Participants with Crohn's Disease (CD) must have been in remission as defined by a Crohn's Disease Activity Index (CDAI) \<150
  3. Participants with ulcerative colitis (UC) must either have been in remission or have had mild disease. Remission was defined as a partial Mayo score of ≤2 with no individual sub-score exceeding 1. Mild disease was defined as a partial Mayo score ≤3 with no individual sub-score exceeding 1 point.
* For participants 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/kilograms/day during this time.
* Participants being administered biologic treatments (for example, anti-tumor necrosis factor 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 participants of childbearing potential must have used ≥1 effective method (≤1% failure rate) of contraception during the trial and until 4 weeks following the last dose of IP (including LTSE 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 (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt).
  * History of, or current, hepatorenal syndrome (type I or II) or Screening serum creatinine \>2 mg/deciliter (178 micromoles/liter \[L\]).
  * Platelet count \<50 x 10\^9/L.
* Current clinical evidence of dominant strictures that were 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 were not considered a safety risk in the opinion of the Investigator might have been 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 cholangitis (PBC), alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, hepatitis B virus (unless seroconverted and no positive Hepatitis B Virus deoxyribonucleic acid), 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 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 participant was on a stable prophylaxis dose for at least 3 months prior to Day 0).
* Administration of the following medications was prohibited ≤6 months of Day 0 and throughout the trial: fenofibrate or other fibrates and potentially hepatotoxic medications (including alpha-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin).
* IBD flare during Screening (up to and including Day 0), where "flare" was 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 had 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 (for example, 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 participants who were 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 was uncertain.