Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment

Phase 4TerminatedNCT03633227

Intercept Pharmaceuticals22 enrolled

Overview

This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics (PK) and safety of OCA treatment in participants with PBC and moderate to severe hepatic impairment over a 48-week treatment period. Participants who have completed their 48-week double blind treatment period will continue double-blind treatment until all randomized participants have completed their 48-week treatment period and the database for that period is locked. An open-label extension study in which all participants receive OCA will be considered following review of blinded safety and PK data.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Liver Cirrhosis, Biliary

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver Diseases \[AASLD\] and European Association for the Study of the Liver \[EASL\] Practice Guidelines, defined as having ≥2 of the following 3 diagnostic factors: * History of elevated alkaline phosphatase (ALP) levels for at least 6 months * Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), PBC specific antibodies (anti-glycoprotein 210 \[GP210\] and/or anti-SP100) and/or antibodies against the major M2 components (E2 component of mitochondrial pyruvate dehydrogenase complex \[PDC-E2\], 2-oxo-glutaric acid dehydrogenase complex) * Liver biopsy consistent with PBC (collected at any time prior to Screening) 2. Evidence of cirrhosis including at least one of the following: * Biopsy results consistent with PBC Stage 4 * Liver stiffness as assessed by Transient Elastography (TE) Median Value ≥16.9 kilopascals (kPa) * Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement of portal vein and splenomegaly) * Combined low platelet count (\<140,000/cubic millimeter \[mm\^3\]) with * persistent decrease in serum albumin, or * elevation in prothrombin time/international normalized ratio (INR) (not due to antithrombotic agent use), or * elevated bilirubin (2\*upper limit of normal \[ULN\]) 3. Satisfy the criteria of the modified Child-Pugh (CP) classification for hepatic impairment during Screening: * Moderate: CP-B (Scores 7 to 9) or * Severe: CP-C (Scores 10 to 12) 4. Model of end-stage liver disease (MELD) score of 6 to 24 at Screening 5. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months) Exclusion Criteria: 1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 2. History of liver transplant or organ transplant 3. History of alcohol or drug abuse within 12 months prior to Screening 4. Hepatic encephalopathy (as defined by a West Haven score of ≥2 5. History or presence of other concomitant liver diseases including: * Hepatitis C virus infection and ribonucleic acid (RNA) positive * Active hepatitis B infection; however, participants 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 * Alcoholic liver disease * Definite autoimmune liver disease or overlap hepatitis * Gilbert's Syndrome 6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization Other inclusion/exclusion criteria may apply.

Locations (40)

Inland Empire Liver Foundation

Rialto, California, United States

University of California, Ddavis Medical Center

Sacramento, California, United States

Schiff Center for Liver Diseases/ University of Miami

Miami, Florida, United States

Mercy Medical Center

Baltimore, Maryland, United States

University Of Michigan

Ann Arbor, Michigan, United States

Outcomes

Primary Outcomes

Maximum Observed Concentration (Cmax) of Total OCA at Week 12

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. Pharmacokinetics (PK) of OCA 5 mg twice weekly or 10 mg twice weekly at Week 12 are not applicable as no participant started 5 mg twice weekly or 10 mg twice weekly at Week 12.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Time to Maximum Concentration (Tmax) of Total OCA at Week 12

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Trough Concentration (Ctrough) of Total OCA at Week 12

Ctrough was considered as the concentration at 24-hours post-dose at Week 12. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: 24 hours post-dose at Week 12

Area Under the Concentration Versus Time Curve From Zero Time to 24 Hours (AUC0-24h) of Total OCA at Week 12

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Cmax of Total OCA at Week 18

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Tmax of Total OCA at Week 18

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Ctrough of Total OCA at Week 18

Ctrough was considered as the concentration at 24-hours post-dose at Week 18. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: 24 hours post-dose at Week 18

AUC0-24h of Total OCA at Week 18

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Cmax of Total OCA at Week 24

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Tmax of Total OCA at Week 24

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Ctrough of Total OCA at Week 24

Ctrough was considered as the concentration at 24-hours post-dose at Week 24. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: 24 hours post-dose at Week 24

AUC0-24h of Total OCA at Week 24

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Cmax of Total OCA at Week 30

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Tmax of Total OCA at Week 30

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Ctrough of Total OCA at Week 30

Ctrough was considered as the concentration at 24-hours post-dose at Week 30. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: 24 hours post-dose at Week 30

AUC0-24h of Total OCA at Week 30

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Cmax of Total OCA at Week 48

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Tmax of Total OCA at Week 48

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Ctrough of Total OCA at Week 48

Ctrough was considered as the concentration at 24-hours post-dose at Week 48. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.

Time frame: 24 hours post-dose at Week 48

AUC0-24h of Total OCA at Week 48

Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Cmax of Unconjugated OCA at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Tmax of Unconjugated OCA at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Ctrough of Unconjugated OCA at Week 12

Ctrough was considered as the concentration at 24-hours post-dose at Week 12.

Time frame: 24 hours post-dose at Week 12

AUC0-24h of Unconjugated OCA at Week 12

AUC0-24 was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Cmax of Unconjugated OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Tmax of Unconjugated OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Ctrough of Unconjugated OCA at Week 18

Ctrough was considered as the concentration at 24-hours post-dose at Week 18.

Time frame: 24 hours post-dose at Week 18

AUC0-24h of Unconjugated OCA at Week 18

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Cmax of Unconjugated OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Tmax of Unconjugated OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Ctrough of Unconjugated OCA at Week 24

Ctrough was considered as the concentration at 24-hours post-dose at Week 24.

Time frame: 24 hours post-dose at Week 24

AUC0-24h of Unconjugated OCA at Week 24

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Cmax of Unconjugated OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Tmax of Unconjugated OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Ctrough of Unconjugated OCA at Week 30

Ctrough was considered as the concentration at 24-hours post-dose at Week 30.

Time frame: 24 hours post-dose at Week 30

AUC0-24h of Unconjugated OCA at Week 30

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Cmax of Unconjugated OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Tmax of Unconjugated OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Ctrough of Unconjugated OCA at Week 48

Ctrough was considered as the concentration at 24-hours post-dose at Week 48.

Time frame: 24 hours post-dose at Week 48

AUC0-24h of Unconjugated OCA at Week 48

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Cmax of Glyco Conjugate of OCA (Glyco-OCA) at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Tmax of Glyco-OCA at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Ctrough of Glyco-OCA at Week 12

Ctrough was considered as the concentration at 24-hours post-dose at Week 12.

Time frame: 24 hours post-dose at Week 12

AUC0-24h of Glyco-OCA at Week 12

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Metabolite to Parent Ratio of AUC-0-24h (MRAUC) of Glyco-OCA at Week 12

MRAUC was the ratio of AUC0-24h of Glyco-OCA (metabolite) to AUC0-24h of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of Glyco-OCA, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Metabolite to Parent Ratio of Cmax (MRCmax) of Glyco-OCA at Week 12

MRCmax was the ratio of Cmax of Glyco-OCA (metabolite) to Cmax of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of Glyco-OCA, where Cmax is the maximum observed concentration.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Cmax of Glyco-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Tmax of Glyco-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Ctrough of Glyco-OCA at Week 18

Ctrough was considered as the concentration at 24-hours post-dose at Week 18.

Time frame: 24 hours post-dose at Week 18

AUC0-24h of Glyco-OCA at Week 18

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRAUC of Glyco-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRCmax of Glyco-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Cmax of Glyco-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Tmax of Glyco-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Ctrough of Glyco-OCA at Week 24

Ctrough was considered as the concentration at 24-hours post-dose at Week 24.

Time frame: 24 hours post-dose at Week 24

AUC0-24h of Glyco-OCA at Week 24

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRAUC of Glyco-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRCmax of Glyco-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Cmax of Glyco-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Tmax of Glyco-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Ctrough of Glyco-OCA at Week 30

Ctrough was considered as the concentration at 24-hours post-dose at Week 30.

Time frame: 24 hours post-dose at Week 30

AUC0-24h of Glyco-OCA at Week 30

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRAUC of Glyco-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRCmax of Glyco-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Cmax of Glyco-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Tmax of Glyco-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Ctrough of Glyco-OCA at Week 48

Ctrough was considered as the concentration at 24-hours post-dose at Week 48.

Time frame: 24 hours post-dose at Week 48

AUC0-24h of Glyco-OCA at Week 48

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRAUC of Glyco-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRCmax of Glyco-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Cmax of Tauro Conjugate of OCA (Tauro-OCA) at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Tmax of Tauro-OCA at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Ctrough of Tauro-OCA at Week 12

Ctrough was considered as the concentration at 24-hours post-dose at Week 12.

Time frame: 24 hours post-dose at Week 12

AUC0-24h of Tauro-OCA at Week 12

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

MRAUC of Tauro-OCA at Week 12

MRAUC was the ratio of AUC0-24h of Tauro-OCA (metabolite) to AUC0-24h of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of Tauro-OCA, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

MRCmax of Tauro-OCA at Week 12

MRCmax was the ratio of Cmax of Tauro-OCA (metabolite) to Cmax of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of Tauro-OCA, where Cmax is the maximum observed concentration.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Cmax of Tauro-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Tmax of Tauro-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Ctrough of Tauro-OCA at Week 18

Ctrough was considered as the concentration at 24-hours post-dose at Week 18.

Time frame: 24 hours post-dose at Week 18

AUC0-24h of Tauro-OCA at Week 18

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRAUC of Tauro-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRCmax of Tauro-OCA at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Cmax of Tauro-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Tmax of Tauro-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Ctrough of Tauro-OCA at Week 24

Ctrough was considered as the concentration at 24-hours post-dose at Week 24.

Time frame: 24 hours post-dose at Week 24

AUC0-24h of Tauro-OCA at Week 24

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRAUC of Tauro-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRCmax of Tauro-OCA at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Cmax of Tauro-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Tmax of Tauro-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Ctrough of Tauro-OCA at Week 30

Ctrough was considered as the concentration at 24-hours post-dose at Week 30.

Time frame: 24 hours post-dose at Week 30

AUC0-24h of Tauro-OCA at Week 30

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRAUC of Tauro-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRCmax of Tauro-OCA at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Cmax of Tauro-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Tmax of Tauro-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Ctrough of Tauro-OCA at Week 48

Ctrough was considered as the concentration at 24-hours post-dose at Week 48.

Time frame: 24 hours post-dose at Week 48

AUC0-24h of Tauro-OCA at Week 48

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRAUC of Tauro-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRCmax of Tauro-OCA at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Cmax of Glucuronide Metabolite of OCA (OCA-glucuronide) at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Tmax of OCA-glucuronide at Week 12

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Ctrough of OCA-glucuronide at Week 12

Ctrough was considered as the concentration at 24-hours post-dose at Week 12.

Time frame: 24 hours post-dose at Week 12

AUC0-24h of OCA-glucuronide at Week 12

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

MRAUC of OCA-glucuronide at Week 12

MRAUC was the ratio of AUC0-24h of OCA-glucuronide (metabolite) to AUC0-24h of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of OCA-glucuronide, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

MRCmax of OCA-glucuronide at Week 12

MRCmax was the ratio of Cmax of OCA-glucuronide (metabolite) to Cmax of OCA (parent drug) \* ratio of molecular weight of OCA to molecular weight of OCA-glucuronide, where Cmax is the maximum observed concentration.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

Cmax of OCA-glucuronide at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Tmax of OCA-glucuronide at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Ctrough of OCA-glucuronide at Week 18

Ctrough was considered as the concentration at 24-hours post-dose at Week 18.

Time frame: 24 hours post-dose at Week 18

AUC0-24h of OCA-glucuronide at Week 18

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRAUC of OCA-glucuronide at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

MRCmax of OCA-glucuronide at Week 18

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

Cmax of OCA-glucuronide at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Tmax of OCA-glucuronide at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Ctrough of OCA-glucuronide at Week 24

Ctrough was considered as the concentration at 24-hours post-dose at Week 24.

Time frame: 24 hours post-dose at Week 24

AUC0-24h of OCA-glucuronide at Week 24

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRAUC of OCA-glucuronide at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

MRCmax of OCA-glucuronide at Week 24

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

Cmax of OCA-glucuronide at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Tmax of OCA-glucuronide at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Ctrough of OCA-glucuronide at Week 30

Ctrough was considered as the concentration at 24-hours post-dose at Week 30.

Time frame: 24 hours post-dose at Week 30

AUC0-24h of OCA-glucuronide at Week 30

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRAUC of OCA-glucuronide at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

MRCmax of OCA-glucuronide at Week 30

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

Cmax of OCA-glucuronide at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Tmax of OCA-glucuronide at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Ctrough of OCA-glucuronide at Week 48

Ctrough was considered as the concentration at 24-hours post-dose at Week 48.

Time frame: 24 hours post-dose at Week 48

AUC0-24h of OCA-glucuronide at Week 48

AUC0-24h was calculated using the linear/linear trapezoidal rule.

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRAUC of OCA-glucuronide at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

MRCmax of OCA-glucuronide at Week 48

Time frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. An SAE was any AE that results in death, was life-threatening, resulted in a persistent or significant disability/incapacity, resulted in in-patient hospitalization or prolonged an existing hospitalization, was a congenital anomaly/birth defect, or was an important medical event that could jeopardize the participant or could have required medical intervention to prevent one of the outcomes listed above. TEAE was defined as any AE if it met one or more of the following criteria: 1) An AE started on or after the first study drug dose and within 30 days after the last dose of study drug, 2) An AE occurred prior to the first study drug dose that worsens (increase in grade) after the first study drug dose.

Time frame: Baseline up to approximately 3 years

Secondary Outcomes

Change From Baseline in the Model of End-stage Liver Disease (MELD) Score at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

The MELD scoring system is used to assess the severity of chronic liver disease. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and prothrombin international normalized ratio (INR): 3.78×log normal (ln) \[total bilirubin (mg/deciliter \[dL\])\] + 11.2×ln\[INR\] + 9.57×ln\[serum creatinine (mg/dL)\] + 6.43. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.

Time frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

Change From Baseline in MELD-Sodium (Na) Score at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

The MELD-Na scoring system is used to assess the severity of chronic liver disease in the participants with an initial MELD(i) score greater than 11. MELD-Na score is derived from the participant's serum total bilirubin, serum creatinine, INR, and sodium. The MELD-Na score is re-calculated as follows: MELD-Na = MELD(i) + 1.32\*(137-Na) - \[0.033\*MELD(i)\*(137-Na)\]. MELD score ranges from 6-40 with higher scores indicating more severe liver disease and a worse outcome. The MELD(i) score is derived from the participant's serum total bilirubin, serum creatinine, and prothrombin international normalized ratio (INR): 3.78×log normal (ln) \[total bilirubin (mg/deciliter \[dL\])\] + 11.2×ln\[INR\] + 9.57×ln\[serum creatinine (mg/dL)\] + 6.43. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.

Time frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

Change From Baseline in Child-Pugh Score at Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

The Child-Pugh classification was a scoring system used for the classification of the severity of cirrhosis. It included three continuous variables (bilirubin, albumin, and INR) and two discrete variables (ascites and encephalopathy). Each variable was scored 1-3 with 3 indicating most severe derangement. The determination of Child-Pugh score ranged from 5 to 15. The higher the score, the sicker the participant.

Time frame: Baseline, Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of Participants by Child-Pugh Score Component Category (Hepatic Encephalopathy Categories)

Number of participants with Child-Pugh component - Hepatic encephalopathy in categories of Grade 0, Grade 1 or 2, and Grade 3 and 4 has been reported. Grade 0: normal consciousness, normal personality, normal neurological examination, normal electroencephalogram. Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles, per second (cps) waves. Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.

Time frame: Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Change From Baseline in Total Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3

Total bile acids (micromole \[μM\]) = total ursodeoxycholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total chenodeoxycholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total deoxycholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total cholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total lithocholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM.

Time frame: Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3

Change From Baseline in Total Endogenous Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3

Total endogenous bile acids (μM) = total chenodeoxycholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total deoxycholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total cholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM + total lithocholic acid (unconjugated, glyco-conjugate, tauro-conjugate) in μM.

Time frame: Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3