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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Primary Sclerosing Cholangitis

Conditions
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Primary Sclerosing Cholangitis (PSC)

Intervention / Treatment
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* Drug: Obeticholic Acid (OCA)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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): Colonoscopy (if participant has a colon) or other appropriate endoscopic procedure within 12 months of Day 0 confirming no dysplasia or colorectal cancer Participants with Crohn's Disease (CD) must have been in remission as defined by a Crohn's Disease Activity Index (CDAI) <150 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.5 mg OCA titrating to 3 mg OCA<br>Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks. | Drug: Obeticholic Acid (OCA)<br> <br> * Other names: INT-747;|
| Experimental: 5 mg OCA titrating to 10 mg OCA<br>Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks. | Drug: Obeticholic Acid (OCA)<br> <br> * Other names: INT-747;|
| Experimental: Placebo<br>Participants randomized to placebo took placebo for 24 weeks during the DB phase. | Drug: Placebo<br> <br> |
| Experimental: LTSE OCA Total<br>Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study. | Drug: Obeticholic Acid (OCA)<br> <br> * Other names: INT-747;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP) | The primary efficacy analysis compared the Week 24 change from Baseline in ALP between OCA treatment group and placebo using an analysis of covariance (ANCOVA) model with fixed effects for treatment group and randomization strata, and Baseline as a covariate. Results are reported in U/L. | Baseline, Week 24 | 
| LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs) | The primary safety analysis evaluated the effects of OCA treatment on AESIs of pruritus, hepatic disorders, and dyslipidemia. All adverse event (AE) summaries were restricted to treatment emergent AEs (TEAEs), which were defined as any AEs that newly appeared, increased in frequency, or worsened in severity following initiation of investigational product. Treatment-emergent pruritus was defined as any preferred term (PT) including Prur-. Hepatic disorder AESIs were defined using specific Hepatic Disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) terms. AE lipid profile changes, defined in the Dyslipidemia SMQ, were reported. Verbatim terms were mapped to PTs and system organ classes (SOCs) using MedDRA version 17.1 for all AE summaries except those for hepatic disorder AESIs, which used MedDRA version 18.1. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | LTSE Baseline (DB Week 24) to Month 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT) | As a marker of hepatic biochemistry and liver function, the median change in ALT from Baseline at Week 24 is reported. Results are reported in U/L. | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST) | As a marker of hepatic biochemistry and liver function, the median change in AST from Baseline at Week 24 is reported. Results are reported in U/L. | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Serum Total Bilirubin | As a marker of hepatic biochemistry and liver function, the median change in serum total bilirubin from Baseline at Week 24 is reported. Results are reported in umol/L. | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Serum Direct Bilirubin | As a marker of hepatic biochemistry and liver function, the median change in serum direct bilirubin from Baseline at Week 24 is reported. Results are reported in umol/L. | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT) | As a marker of hepatic biochemistry and liver function, the median change in serum GGT from Baseline at Week 24 is reported. Results are reported in U/L. | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19) | To assess farnesoid X receptor (FXR) activity, the change in FGF-19 from Baseline at Week 24 is reported. Results are reported in picograms/milliliter (pg/mL). | Baseline, Week 24 | 
| DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4) | To assess FXR activity, the change in plasma C4 from Baseline at Week 24 is reported. Results are reported in nanograms (ng)/mL. | Baseline, Week 24 | 
| LTSE Phase: Change From Baseline In Serum ALP At Month 12 | The median change in serum ALP from Baseline to the last available visit is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Serum ALT At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in ALT from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Serum AST At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in AST from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Serum Total Bilirubin At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in serum total bilirubin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Serum Direct Bilirubin At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in serum direct bilirubin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Serum GGT At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in serum GGT from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Albumin At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in albumin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in grams (g)/L. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In INR At Month 12 | As a marker of hepatic biochemistry and liver function, the median change in INR from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Transient Elastography (TE) At Month 12 | As a marker of hepatic inflammation and fibrosis, the median change in TE, as a measure of hepatic stiffness, from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in kilopascal (kPa). | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Enhanced Liver Fibrosis (ELF) At Month 12 | As a marker of hepatic inflammation and fibrosis, the change in ELF score from Baseline at Month 12 is reported. The ELF score and its components (hyaluronic acid [HA]; procollagen-3 N-terminal peptide [P3NP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) was calculated as follows: 2.278 + 0.851 x ln(HA (ng/mL)) + 0.751 x ln(P3NP (ng/mL)) + 0.394 x ln(TIMP-1 (ng/mL). The DB value at Week 24 was used as the Baseline. An increase in score indicates an improvement/worsening of symptoms. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Plasma FGF-19 At Month 12 | To assess FXR activity, the change in FGF-19 from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in pg/mL. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Change From Baseline In Plasma C4 At Month 12 | To assess FXR activity, the change in plasma C4 from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in ng/mL. | LTSE Baseline (DB Week 24), Month 12 | 
| LTSE Phase: Participants Experiencing Ulcerative Colitis Remission At Month 12 | To assess inflammatory bowel disease (IBD) activity, the number of participants experiencing ulcerative colitis remission at Month 12 is reported. Remission was defined as a partial Mayo score of ≤2 with no individual sub-score exceeding 1 point. | Month 12 | 
| LTSE Phase: Participants Experiencing Crohn's Disease Remission At Month 12 | To assess IBD activity, the number of participants experiencing Crohn's Disease remission at Month 12 is reported. Remission was defined as a Crohn's Disease Activity Index score of <150. | Month 12 | 
| LTSE Phase: Change From Baseline In Total Bile Acids At Month 12 | To assess the effects on bile acids, the median change in total bile acids from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L. | Month 12 | 
| LTSE Phase: Change From Baseline In Pruritus Visual Analogue Scale (VAS) At Month 12 | To assess the effects on disease-specific symptoms, the median change in the pruritus VAS score from Baseline at Month 12 is reported. The score is derived from the VAS participant questionnaire, which has the participant draw a line anywhere on a scale that best represents the severity of the itch; the scale ranges from 0 (no itching) to 10 (worst possible itching), in increments of 2. An increase in score represents an increase in severity of symptoms. The DB value at Week 24 was used as the Baseline. | LTSE Baseline (DB Week 24), Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSC