Clinical Trials/NCT03633227

NCT03633227

Terminated

Phase 4

A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment

Intercept Pharmaceuticals39 sites in 12 countries22 target enrollmentJune 22, 2018

ConditionsLiver Cirrhosis, Biliary

InterventionsObeticholic Acid (OCA)Placebo

DrugsObeticholic Acid (OCA)Placebo

Overview

Phase: Phase 4
Intervention: Obeticholic Acid (OCA)
Conditions: Liver Cirrhosis, Biliary
Sponsor: Intercept Pharmaceuticals
Enrollment: 22
Locations: 39
Primary Endpoint: Tmax of Total OCA at Week 24
Status: Terminated
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Registry

clinicaltrials.gov

Start Date

June 22, 2018

End Date

July 9, 2021

Last Updated

3 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Intercept Pharmaceuticals

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•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)
•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

Exclusion Criteria

•Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6)
•History of liver transplant or organ transplant
•History of alcohol or drug abuse within 12 months prior to Screening
•Hepatic encephalopathy (as defined by a West Haven score of ≥2
•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

Arms & Interventions

Obeticholic Acid (OCA)

Participants will initiate treatment with OCA 5 milligrams (mg) tablets orally once weekly. At Week 12, if there are no safety concerns, the dose will be up-titrated to OCA 5 mg twice weekly. Every 6 weeks thereafter, based on tolerability assessments, further up-titration of dose will be considered. At each titration visit, the participants will start the higher dose regimen no earlier than 2 days after the prior dose. The maximum dose titration will be OCA 10 mg twice weekly at least 3 days apart. The minimum treatment duration will be 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).

Intervention: Obeticholic Acid (OCA)

Placebo

Participants will receive OCA matching placebo orally once weekly or twice weekly for the duration of at least 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).

Intervention: Placebo

Outcomes

Primary Outcomes

Tmax of Total 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

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

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

AUC0-24h 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

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

Ctrough of Unconjugated OCA at Week 24

Time Frame: 24 hours post-dose at Week 24

Ctrough was considered as the concentration at 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

Maximum Observed Concentration (Cmax) of Total 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

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.

Tmax of Total 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

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

Tmax of Total 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

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

Ctrough of Unconjugated OCA at Week 12

Time Frame: 24 hours post-dose at Week 12

Ctrough was considered as the concentration at 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

AUC0-24h 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

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

AUC0-24h 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

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

Trough Concentration (Ctrough) of Total OCA at Week 12

Time Frame: 24 hours post-dose 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 to Maximum Concentration (Tmax) of Total 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

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

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

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

Cmax of Total 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

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

Tmax of Total 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

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

Cmax of Total 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

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

Ctrough of Total OCA at Week 24

Time Frame: 24 hours post-dose 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.

Cmax of Total 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

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

AUC0-24h of Total 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

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

Ctrough of Total OCA at Week 18

Time Frame: 24 hours post-dose 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.

AUC0-24h of Total 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

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

AUC0-24h of Total 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

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

Ctrough of Total OCA at Week 30

Time Frame: 24 hours post-dose 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.

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

AUC0-24h 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

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

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

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

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.

Ctrough of Glyco-OCA at Week 30

Time Frame: 24 hours post-dose at Week 30

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

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

Cmax of Total 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

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

Ctrough of Total OCA at Week 48

Time Frame: 24 hours post-dose 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.

AUC0-24h of Total 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

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

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

Ctrough of Unconjugated OCA at Week 18

Time Frame: 24 hours post-dose at Week 18

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

AUC0-24h 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

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

Ctrough of Unconjugated OCA at Week 30

Time Frame: 24 hours post-dose at Week 30

Ctrough was considered as the concentration at 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

Ctrough of Unconjugated OCA at Week 48

Time Frame: 24 hours post-dose at Week 48

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

AUC0-24h 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

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

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 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 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

Metabolite to Parent Ratio of Cmax (MRCmax) 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 18

Time Frame: 24 hours post-dose at Week 18

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

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

AUC0-24h 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

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

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

Metabolite to Parent Ratio of AUC-0-24h (MRAUC) 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

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.

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 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

Time Frame: 24 hours post-dose at Week 12

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

AUC0-24h 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

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

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

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

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

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

Ctrough of Glyco-OCA at Week 24

Time Frame: 24 hours post-dose at Week 24

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

AUC0-24h 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

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

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

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

AUC0-24h 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

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

MRAUC 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

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.

MRCmax 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

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.

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

Time Frame: 24 hours post-dose at Week 18

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

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

Time Frame: 24 hours post-dose at Week 24

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

AUC0-24h 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

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

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

AUC0-24h 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

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

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

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

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

Ctrough of Glyco-OCA at Week 48

Time Frame: 24 hours post-dose at Week 48

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

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

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

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

AUC0-24h 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

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

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

Ctrough of Tauro-OCA at Week 12

Time Frame: 24 hours post-dose at Week 12

Ctrough was considered as the concentration at 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

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

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

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

AUC0-24h 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

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

AUC0-24h 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

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

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-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-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 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 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 12

Time Frame: 24 hours post-dose at Week 12

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

AUC0-24h 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

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

Ctrough of OCA-glucuronide at Week 18

Time Frame: 24 hours post-dose at Week 18

Ctrough was considered as the concentration at 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

Ctrough of Tauro-OCA at Week 30

Time Frame: 24 hours post-dose at Week 30

Ctrough was considered as the concentration at 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

Ctrough of Tauro-OCA at Week 48

Time Frame: 24 hours post-dose at Week 48

Ctrough was considered as the concentration at 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

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

MRAUC 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

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.

MRCmax 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

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.

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

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

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

AUC0-24h 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

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

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

Time Frame: 24 hours post-dose at Week 24

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

AUC0-24h 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

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

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

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

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

Ctrough of OCA-glucuronide at Week 30

Time Frame: 24 hours post-dose at Week 30

Ctrough was considered as the concentration at 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

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

Ctrough of OCA-glucuronide at Week 48

Time Frame: 24 hours post-dose at Week 48

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

AUC0-24h 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

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

AUC0-24h 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

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

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

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

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

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

Time Frame: Baseline up to approximately 3 years

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.

Secondary Outcomes

Number of Participants by Child-Pugh Score Component Category (Ascites Categories)(Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15)
Change From Baseline in Aspartate Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Total Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3(Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3)
Change From Baseline in Fibroblast Growth Factor-19 (FGF-19) Concentrations at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3(Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3)
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(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(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 (Prothrombin Time Categories)(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 (Serum Albumin Categories)(Day 1, Weeks 6, 12, 18, 24, 30, 36, 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(Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15)
Number of Participants by Child-Pugh Score Component Category (Total Bilirubin Categories)(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)(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 Bilirubin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Direct Bilirubin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Alkaline Phosphatase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Platelets at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Total Endogenous Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3(Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3)
Change From Baseline in 7α-hydroxy-4-cholesten-3-one (C4) at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3(Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3)
Change From Baseline in Alanine Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Gamma Glutamyl Transferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Prothrombin INR at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Creatinine at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(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 Albumin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15(Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15)