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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02177136

Acronym

AESOP

Enrollment

Registered

2014-06-27

Start date

2015-02-09

Completion date

2018-03-22

Last updated

2021-07-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Primary Sclerosing Cholangitis (PSC)

Keywords

PSC

Brief summary

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

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).

Interventions

DRUGObeticholic Acid (OCA)

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the open-label LTSE phase.

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)	Baseline, Week 24	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.
LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)	LTSE Baseline (DB Week 24) to Month 26	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.

Secondary

Measure	Time frame	Description
DB Phase: Change From Baseline In Serum Total Bilirubin	Baseline, Week 24	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.
DB Phase: Change From Baseline In Serum Direct Bilirubin	Baseline, Week 24	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.
DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)	Baseline, Week 24	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.
DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)	Baseline, Week 24	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).
DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)	Baseline, Week 24	To assess FXR activity, the change in plasma C4 from Baseline at Week 24 is reported. Results are reported in nanograms (ng)/mL.
LTSE Phase: Change From Baseline In Serum ALP At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Serum ALT At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Serum AST At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Serum Total Bilirubin At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Serum Direct Bilirubin At Month 12	LTSE Baseline (DB Week 24), 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.
DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)	Baseline, Week 24	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.
LTSE Phase: Change From Baseline In Albumin At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In INR At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Transient Elastography (TE) At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Enhanced Liver Fibrosis (ELF) At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Plasma FGF-19 At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Plasma C4 At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Participants Experiencing Ulcerative Colitis Remission At Month 12	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.
LTSE Phase: Participants Experiencing Crohn's Disease Remission At Month 12	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.
LTSE Phase: Change From Baseline In Total Bile Acids At Month 12	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.
LTSE Phase: Change From Baseline In Pruritus Visual Analogue Scale (VAS) At Month 12	LTSE Baseline (DB Week 24), 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 Phase: Change From Baseline In Serum GGT At Month 12	LTSE Baseline (DB Week 24), 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.
DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)	Baseline, Week 24	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.

Countries

Italy, United States

Participant flow

Recruitment details

Recruitment started December 2014 and completed September 2016. All participants were required to undergo thorough screening procedures, to confirm they met the eligibility criteria, during the 30-day period preceding the first dose.

Pre-assignment details

Double-blind (DB) Phase: 77 participants were randomly allocated to treatment with placebo, 1.5 milligrams (mg) obeticholic acid (OCA) titrated to 3 mg OCA, or 5 mg OCA titrated to 10 mg OCA; however, 1 participant did not receive treatment. Long-term Safety Extension (LTSE): Open-label OCA doses up to 10 mg daily were evaluated.

Participants by arm

Arm	Count
1.5 mg OCA Titrating to 3 mg OCA Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.	25
5 mg OCA Titrating to 10 mg OCA Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.	26
Placebo Participants randomized to placebo took placebo for 24 weeks.	25
Total	76

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
DB Phase	Adverse Event	3	2	3	0
DB Phase	Discontinued Due to Pruritus	1	3	0	0
DB Phase	Protocol Violation	0	0	1	0
DB Phase	Withdrawal by Subject	2	0	0	0
DB Phase	Withdrew Consent Prior to Dosing	1	0	0	0
LTSE Phase	Adverse Event	0	0	0	10
LTSE Phase	Discontinued Due to Pruritus	0	0	0	4
LTSE Phase	Lost to Follow-up	0	0	0	1
LTSE Phase	Participant Moved	0	0	0	1
LTSE Phase	Physician Decision	0	0	0	2
LTSE Phase	Withdrawal by Subject	0	0	0	6

Baseline characteristics

Characteristic	1.5 mg OCA Titrating to 3 mg OCA	5 mg OCA Titrating to 10 mg OCA	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	3 Participants	1 Participants	5 Participants
Age, Categorical Between 18 and 65 years	24 Participants	23 Participants	24 Participants	71 Participants
Age, Continuous	41.6 years STANDARD_DEVIATION 12.56	44.9 years STANDARD_DEVIATION 14.28	43.7 years STANDARD_DEVIATION 13.05	43.4 years STANDARD_DEVIATION 13.22
Alkaline phosphatase (ALP)	422.5 units/liter (U/L) STANDARD_DEVIATION 123.07	428.5 units/liter (U/L) STANDARD_DEVIATION 178.19	562.8 units/liter (U/L) STANDARD_DEVIATION 300.22	470.7 units/liter (U/L) STANDARD_DEVIATION 220.2
Body Mass Index	24.6 kg/meter squared STANDARD_DEVIATION 4.38	25.3 kg/meter squared STANDARD_DEVIATION 3.74	24.5 kg/meter squared STANDARD_DEVIATION 3.71	24.8 kg/meter squared STANDARD_DEVIATION 3.92
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	2 Participants	1 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants	24 Participants	24 Participants	71 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Height	174.4 centimeter STANDARD_DEVIATION 8.95	170.4 centimeter STANDARD_DEVIATION 11.61	172.6 centimeter STANDARD_DEVIATION 10.7	172.4 centimeter STANDARD_DEVIATION 10.49
International Normalized Ratio (INR)	1.0 ratio STANDARD_DEVIATION 0.06	1.0 ratio STANDARD_DEVIATION 0.1	1.0 ratio STANDARD_DEVIATION 0.07	1.0 ratio STANDARD_DEVIATION 0.08
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	3 Participants	4 Participants	3 Participants	10 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	21 Participants	22 Participants	22 Participants	65 Participants
Sex: Female, Male Female	10 Participants	14 Participants	11 Participants	35 Participants
Sex: Female, Male Male	15 Participants	12 Participants	14 Participants	41 Participants
Total Bilirubin	16.3 micromoles (umol)/L STANDARD_DEVIATION 8.17	19.4 micromoles (umol)/L STANDARD_DEVIATION 10.94	20.9 micromoles (umol)/L STANDARD_DEVIATION 11.48	18.9 micromoles (umol)/L STANDARD_DEVIATION 10.35
Weight	74.5 kilograms (kg) STANDARD_DEVIATION 12.51	73.6 kilograms (kg) STANDARD_DEVIATION 12.76	73.0 kilograms (kg) STANDARD_DEVIATION 12.95	73.7 kilograms (kg) STANDARD_DEVIATION 12.59

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 25	0 / 27	0 / 24	0 / 59
other Total, other adverse events	20 / 25	24 / 27	21 / 24	53 / 59
serious Total, serious adverse events	4 / 25	4 / 27	2 / 24	19 / 59

Outcome results

Primary

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.

Time frame: Baseline, Week 24

Population: Intent-to-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)	-105.05 U/L	Standard Error 38.02
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)	-110.19 U/L	Standard Error 33.77
Placebo	DB Phase: Change From Baseline In Serum Alkaline Phosphatase (ALP)	-26.76 U/L	Standard Error 36.65

p-value: 0.0434ANCOVA

p-value: 0.0665ANCOVA

Primary

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.

Time frame: LTSE Baseline (DB Week 24) to Month 26

Population: LTSE Population: All participants who received any amount of investigational product during the LTSE phase.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
1.5 mg OCA Titrating to 3 mg OCA	LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)	Dyslipidaemia	1 Participants
1.5 mg OCA Titrating to 3 mg OCA	LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)	Hepatic Disorder	23 Participants
1.5 mg OCA Titrating to 3 mg OCA	LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)	Pruritus	34 Participants

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-To-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)	-2.80 ng/mL
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)	-2.90 ng/mL
Placebo	DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)	0.05 ng/mL

Secondary

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).

Time frame: Baseline, Week 24

Population: Intent-to-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)	32.00 pg/mL
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)	147.00 pg/mL
Placebo	DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)	-19.50 pg/mL

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-To-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)	-33.0 U/L
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)	-5.5 U/L
Placebo	DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)	-19.5 U/L

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-to-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)	-8.0 U/L
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)	0.5 U/L
Placebo	DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)	-14.0 U/L

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-To-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Direct Bilirubin	0.8 umol/L
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Direct Bilirubin	0.9 umol/L
Placebo	DB Phase: Change From Baseline In Serum Direct Bilirubin	0.0 umol/L

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-To-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)	-79.0 U/L
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)	-78.5 U/L
Placebo	DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)	-89.0 U/L

Secondary

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.

Time frame: Baseline, Week 24

Population: Intent-To-Treat Population: All randomized participants who received any amount of investigational product within the DB phase.

Arm	Measure	Value (MEDIAN)
1.5 mg OCA Titrating to 3 mg OCA	DB Phase: Change From Baseline In Serum Total Bilirubin	0.8 umol/L
5 mg OCA Titrating to 10 mg OCA	DB Phase: Change From Baseline In Serum Total Bilirubin	1.3 umol/L
Placebo	DB Phase: Change From Baseline In Serum Total Bilirubin	0.0 umol/L

Secondary

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.

Time frame: LTSE Baseline (DB Week 24), Month 12