Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

To assess the effect of OCA, compared to placebo in conjunction with the established local standard of care, on clinical outcomes in participants with PBC as measured by time to the first occurrence of any of the following adjudicated events, derived as a composite event endpoint of death, liver transplant, model of end-stage liver disease (MELD) ≥15, uncontrolled ascites, or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), or spontaneous bacterial peritonitis. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% confidence intervals (CIs) for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

Population: The Intent-to-Treat (ITT) population included all randomized participants who received any dosage of OCA or placebo.

Primary clinical outcome event is the first occurrence of the following events: death, liver transplant, MELD score \>=15 (MELD-Na score \>=12 baseline), MELD-Na score \>=15 (MELD-Na score \<12 baseline), hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis), or bacterial empyema, uncontrolled or refractory ascites (requiring large volume paracentesis), portal hypertension syndromes, progression to decompensated liver disease, and progression to clinical evidence of portal hypertension without decompensation (for participants without decompensation or clinical evidence of portal hypertension at baseline). 71 endpoint events were observed in the OCA arm, and 80 were observed in the Placebo arm. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes ALT, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes albumin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes ALP, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes AST, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes direct bilirubin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes GGT, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The coagulation test, which includes INR, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. INR is the ratio of tested prothrombin time to normal prothrombin time, to a power designated the international sensitivity index (ISI). INR normal range is 0.8 to 1.2 (female and male). Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver biochemistry, which includes total bilirubin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using mixed model repeated measures (MMRM), including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of hepatic fibrosis, which include C4, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Child-Pugh Score (Pugh 1973, Lucey 1997) was calculated and reported within the electronic data capture (EDC) system based on data entered into the CRF by adding the scores from the 5 factors and could have ranged from 5 to15. A total score of 5 to 6 was considered Grade A (mild, well-compensated disease); 7 to 9 was Grade B (moderate, significant functional compromise); and 10 and above was Grade C (severe, decompensated disease).

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of inflammation, which include CRP, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of inflammation, which include CK-18, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Liver fibrosis was assessed using ELF test. The ELF test assessed: hyaluronic acid, procollagen3 N-terminal peptide, and a tissue inhibitor of metalloproteinase 1. The ELF test is a composite score: \< 7.7: no to mild fibrosis; ≥ 7.7 - \< 9.8: Moderate fibrosis; ≥ 9.8 - \< 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline suggests decreased fibrosis.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of hepatic fibrosis, which include FGF-19, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of inflammation, which include IgM, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo

Hepatic stiffness was measured using non-invasive transient Elastography with Fibroscan® TE device.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Mayo Risk Score (MRS) was calculated and reported within the EDC system. Calculation of MRS included Investigator assessment of peripheral edema and the use of diuretic therapy, which was assessed during the adverse event and concomitant medicine review at the scheduled visits and entered into the CRF, as well as total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. There is no maximum and minimum range of score but an increase in the MRS represents an increase in the risk of death.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The MELD-Na score is another useful predictor in assessing participants with significant decompensation. The MELD-Na took into account the effect of serum sodium as a reflection of renal function and hypothetically may improve the accuracy of the model score. The MELD-Na score is derived from the participant's serum total bilirubin, serum creatinine, INR, and serum sodium, as appropriate, to predict survival. The MELD-Na score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and INR, as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Markers of inflammation, which include TNF-α, were assessed.

Time frame: Baseline up to Month 72

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

An adverse event (AE) was defined as any unfavorable and unintended sign (for example, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or procedure, whether or not considered related to the medicinal product or procedure, which occurred during the course of the clinical study. TEAEs were defined as AEs that occurred on or after the date and time of study drug administration, or those that first occurred before dosing but worsened in frequency or severity after study drug administration. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.

Time frame: Baseline up to the last IP dose plus 30 days and prior to commercial OCA initiation date (up to 7 years)

Population: The safety population consisted of all participants who received any amount of OCA or placebo. Treatment assignment based on the treatment received before any initiation of commercial OCA.

The fasting trough PK concentrations of OCA of different dose regimens taken throughout the study are reported.

Time frame: Months 3, 6, 9, 12, 24, 36, 48, and 60

Population: The PK Population included all OCA participants who had at least 1 confirmed fasted analyzable sample.

In Month 9, blood samples were collected at predose, 0.5h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4h, 5 h, and 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose, 0.5h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4h, 5 h, and 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4h, 5 h, and 6 h and PK serial concentrations at different dose regimen are reported.

Time frame: Month 9

Population: The PK Population included all OCA participants who had at least 1 confirmed fasted analyzable sample. Participants fasted for approximately 8 hours prior to the visit and had no major protocol deviations that potentially affected exposure levels.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with CP Score=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg Q2W OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 10 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with CP Score=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QD OCA with MELD Category=B.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with CP Score=NC.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 9, blood samples were collected at predose to 6 h for PK analysis in participants who received 5 mg QOD OCA with MELD Category=A.

Time frame: Month 9

Population: Participants in the PK population that had the appropriate CP Score, had received the assigned dosage according to the dosage regimen and had an analyzable sample at month 9.

In Month 6, the trough concentration of OCA in the cirrhotic participants who received 10 mg Q2W OCA was reported.

Time frame: Month 6

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the cirrhotic participants who received 10 mg QD OCA was reported.

Time frame: Months 6, 9, 12, 24, 36, and 60

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

Time frame: Months 3, 6, 9, 12, 24, 36, 48, and 60

Population: No participant was tested for this outcome measure.

The trough concentration of OCA in the cirrhotic participants who received 5 mg Q2W OCA was reported.

Time frame: Months 6, 24, 36 and 48

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the cirrhotic participants who received 5 mg QD OCA was reported.

Time frame: Months 3, 6, 12, 24, and 48

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose

The trough concentration of OCA in the cirrhotic participants who received 5 mg QOD OCA was reported.

Time frame: Months 6, 12, and 24

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the cirrhotic participants who received 5 mg QW OCA was reported.

Time frame: Months 6 and 12

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

In Month 6, the trough concentration of OCA in the non-cirrhotic participants who received 10 mg Q2W OCA was reported.

Time frame: Month 6

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the non-cirrhotic participants who received 10 QD QOD OCA was reported.

Time frame: Months 6, 9, 12, 24, and 36

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

In Month 12, the trough concentration of OCA in the non-cirrhotic participants who received 10 mg QOD OCA was reported.

Time frame: Month 12

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the non-cirrhotic participants who received 5 Q2W QOD OCA was reported.

Time frame: Months 3, 6, 12, 24, 36, and 48

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the non-cirrhotic participants who received 5 mg QD OCA was reported.

Time frame: Months 3, 6, 9, 12, and 24

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

The trough concentration of OCA in the non-cirrhotic participants who received 5 mg QOD OCA was reported.

Time frame: Months 3, 6, and 12

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

In Month 12, the trough concentration of OCA in the non-cirrhotic participants who received 5 QW QOD OCA was reported.

Time frame: Month 12

Population: Participants in the PK population that had data available for cirrhosis status, mean trough concentrations by presence or absence of cirrhosis and dose.

When a participant is identified as noncirrhotic at the Baseline and exhibited any signs or symptoms associated with progression to cirrhosis, the participant was assessed by Fibroscan® TE where available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of cirrhosis, liver transplant or death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to development of varix/varices was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented development of varix/varices, liver transplant or death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The results represent the ratio of OCA to placebo. The fatal events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the fatal events distribution percentiles (25th and 50th) are provided

Time frame: Time to first occurrence from date of randomization until the date of death from any cause (up to 7 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Hospitalization events include new onset or recurrent variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis OR presence of \>250/mm\^3 polymorph leucocytes \[PMNs\] in the ascitic fluid), bacterial empyema is confirmed by diagnostic thoracentesis OR presence of \>250/mm\^3 PMNs in the pleural fluid. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of hospitalization, liver transplant or death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to occurrence of a liver transplant was assessed. The results represented the ratio of OCA to placebo. A hazard ratio \<1 indicated an advantage for OCA. The event of interest was summarized through Cumulative Incidence Function (CIF) estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and International Normalized Ratio (INR), as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented MELD Score ≥15, liver transplant or date of death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The first occurrence of the key secondary clinical event refers to the first occurrence of the following events: death, liver transplant, MELD-Na score \>=15 if MELD-Na\< 12 at baseline, MELD score \>=15 if MELD-Na \>=12 at baseline, uncontrolled or refractory ascites, portal hypertension syndromes (hepatorenal syndrome, portopulmonary syndrome, hepatopulmonary syndrome) or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis, or bacterial empyema. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up to 7 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

Uncontrolled or refractory ascites are defined as diuretic-resistant ascites requiring large-volume paracentesis. The effect of OCA compared to placebo on time to the first occurrence of uncontrolled or refractory ascites was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented uncontrolled or refractory ascites, liver transplant or date of death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to liver-related death was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first liver-related or non-liver- related death, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to liver-related death, liver transplant, or MELD Score ≥15 was assessed. The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and INR, as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of liver transplant, liver-related death, non-liver-related death from any cause or MELD Score ≥15, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to liver-related death or liver transplant was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of liver transplant, liver-related death or non-liver-related death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to liver transplant or death (all-cause) was assessed. The events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 7 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.

The effect of OCA compared to placebo on time to occurrence of HCC was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of HCC diagnosis, liver transplant or death from any cause, whichever came first (up to 5 years)

Population: The ITT population included all randomized participants who received any dosage of OCA or placebo.