Trial Outcomes & Findings for Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (NCT NCT02308111)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

334 participants

Primary outcome timeframe

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

Results posted on

2023-03-09

Participant Flow

A total of 334 participants were randomized into the study. The study was terminated early as the Data Monitoring Committee made the recommendation not to pursue further enrollment, given the lack of feasibility for this post-marketing study as designed. At termination, the study randomized \<80% of planned enrollment.

Participant milestones

Participant milestones
Measure	Obeticholic Acid Participants received obeticholic acid (OCA) 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and Child-Pugh \[CP\] Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Overall Study STARTED	168	166
Overall Study Received at Least 1 Dose of Study Drug	168	166
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	168	166

Reasons for withdrawal

Reasons for withdrawal
Measure	Obeticholic Acid Participants received obeticholic acid (OCA) 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and Child-Pugh \[CP\] Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Overall Study Adverse Event	31	19
Overall Study Death	9	6
Overall Study Lost to Follow-up	2	7
Overall Study Physician Decision	6	17
Overall Study Protocol Violation	0	1
Overall Study Withdrawal by Subject	28	38
Overall Study Study Terminated by Sponsor	72	61
Overall Study Initiated Commercial OCALIVA	6	8
Overall Study Site Closure	3	3
Overall Study Non-compliance with Study Drug	3	1
Overall Study COVID-19 Pandemic Limitation	2	0
Overall Study Liver Transplant	3	3
Overall Study Liver Transplant Waitlist	2	2
Overall Study Early Termination As Subject Was Randomized Without Meeting All Eligibility Criteria	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.	Total n=334 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	140 Participants n=5 Participants	140 Participants n=7 Participants	280 Participants n=5 Participants
Age, Categorical >=65 years	28 Participants n=5 Participants	26 Participants n=7 Participants	54 Participants n=5 Participants
Age, Continuous	53.4 years STANDARD_DEVIATION 10.28 • n=5 Participants	53.9 years STANDARD_DEVIATION 10.41 • n=7 Participants	53.7 years STANDARD_DEVIATION 10.33 • n=5 Participants
Sex: Female, Male Female	151 Participants n=5 Participants	149 Participants n=7 Participants	300 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants n=5 Participants	18 Participants n=7 Participants	42 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	138 Participants n=5 Participants	139 Participants n=7 Participants	277 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Asian	11 Participants n=5 Participants	9 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	146 Participants n=5 Participants	143 Participants n=7 Participants	289 Participants n=5 Participants
Race (NIH/OMB) More than one race	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	9 Participants n=7 Participants	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to the First Occurrence of Composite Endpoint 25th Percentile	1092 days Interval 670.0 to 1464.0	970 days Interval 688.0 to 1342.0
Time to the First Occurrence of Composite Endpoint 50th Percentile	NA days Interval 1910.0 to NA= Not calculable due to insufficient clinical events. The upper 95% CI limit was not estimable due to an insufficient number of participants with clinical events, as indicated by NA.	NA days NA= Not calculable due to insufficient clinical events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with clinical events, as indicated by NA.

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to the First Occurrence of Primary Clinical Event (Expanded Endpoint) 25th Percentile	370 days Interval 261.0 to 638.0	450 days Interval 358.0 to 569.0
Time to the First Occurrence of Primary Clinical Event (Expanded Endpoint) 50th Percentile	1827 days Interval 1198.0 to The upper 95% CI limit was not estimable due to an insufficient number of participants with clinical events, as indicated by NA	1102 days Interval 841.0 to The upper 95% CI limit was not estimable due to an insufficient number of participants with clinical events, as indicated by NA

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To First Occurrence Of Severe Decompensating Events of Expanded Composite Endpoint 25th Percentile	1092 days Interval 670.0 to 1408.0	929 days Interval 679.0 to 1342.0
Time To First Occurrence Of Severe Decompensating Events of Expanded Composite Endpoint 50th Percentile	NA days Interval 1910.0 to NA= Not calculable due to insufficient clinical events. The upper 95% CI limit was not estimable due to an insufficient number of participants with clinical events, as indicated by NA.	NA days NA= Not calculable due to insufficient clinical events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with clinical events, as indicated by NA.

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Liver Transplant Or Death (All-cause) 25th Percentile	1580 days Interval 1275.0 to The upper 95% CI limit was not estimable due to an insufficient number of participants with events, as indicated by NA.	1803 days Interval 1206.0 to The upper 95% CI limit was not estimable due to an insufficient number of participants with events, as indicated by NA.
Time To Liver Transplant Or Death (All-cause) 50th Percentile	NA days NA= Not calculable due to insufficient events The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with events, as indicated by NA.	NA days NA= Not calculable due to insufficient events The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with events, as indicated by NA.

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to First Occurrence of Fatal Event (All-Cause) 25th Percentile	NA days NA= Not calculable due to insufficient fatal events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with fatal events, as indicated by NA.	NA days NA= Not calculable due to insufficient fatal events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with fatal events, as indicated by NA.
Time to First Occurrence of Fatal Event (All-Cause) 50th Percentile	NA days NA= Not calculable due to insufficient fatal events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with fatal events, as indicated by NA.	NA days NA= Not calculable due to insufficient fatal events. The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with fatal events, as indicated by NA.

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to First Occurrence of Liver Transplant	0.18 proportion of participants Interval 0.11 to 0.26	0.16 proportion of participants Interval 0.09 to 0.23

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to First Occurrence of Hospitalization Due to Hepatic Events	0.11 proportion of participants Interval 0.06 to 0.17	0.18 proportion of participants Interval 0.1 to 0.26

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to First Occurrence of Uncontrolled or Refractory Ascites	0.02 proportion of participants Interval 0.01 to 0.05	0.04 proportion of participants Interval 0.01 to 0.08

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time to First Occurrence of MELD Score ≥15	0.13 proportion of participants Interval 0.07 to 0.19	0.18 proportion of participants Interval 0.11 to 0.25

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Development Of Varix/Varices	0.07 proportion of participants Interval 0.03 to 0.12	0.09 proportion of participants Interval 0.04 to 0.17

SECONDARY outcome

Timeframe: 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 was assessed. The event of interest was summarized through CIF estimate at 5 years.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Liver-Related Death	0.03 proportion of participants Interval 0.01 to 0.07	0.04 proportion of participants Interval 0.01 to 0.09

SECONDARY outcome

Timeframe: 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-related death or liver transplant was assessed. The event of interest was summarized through CIF estimate at 5 years.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Liver-Related Death Or Liver Transplant	0.20 proportion of participants Interval 0.13 to 0.29	0.19 proportion of participants Interval 0.12 to 0.27

SECONDARY outcome

Timeframe: 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, 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Liver-Related Death, Liver Transplant, Or MELD Score ≥15	0.25 proportion of participants Interval 0.17 to 0.33	0.29 proportion of participants Interval 0.21 to 0.37

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=78 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=62 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Progression To Cirrhosis (for Noncirrhotic Subjects at Baseline)	0.07 proportion of participants Interval 0.02 to 0.16	0.15 proportion of participants Interval 0.06 to 0.27

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Time To Occurrence Of Hepatocellular Carcinoma (HCC)	0 proportion of participants The lower and upper 95% CI limits were not estimable due to an insufficient number of participants with events, as indicated by NA.	0.01 proportion of participants Interval 0.0 to 0.05

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Total Bilirubin Month 6	0.10 mg/dL Standard Error 0.069	0.17 mg/dL Standard Error 0.069
Change From Baseline To Month 24 Of Total Bilirubin Month 12	0.26 mg/dL Standard Error 0.113	0.29 mg/dL Standard Error 0.111
Change From Baseline To Month 24 Of Total Bilirubin Month 24	0.30 mg/dL Standard Error 0.141	0.63 mg/dL Standard Error 0.138

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Direct Bilirubin Month 6	0.11 mg/dL Standard Error 0.054	0.14 mg/dL Standard Error 0.054
Change From Baseline To Month 24 Of Direct Bilirubin Month 12	0.13 mg/dL Standard Error 0.073	0.22 mg/dL Standard Error 0.071
Change From Baseline To Month 24 Of Direct Bilirubin Month 24	0.19 mg/dL Standard Error 0.107	0.48 mg/dL Standard Error 0.106

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Aspartate Aminotransferase (AST) Month 6	-14.5 U/L Standard Error 2.21	-0.6 U/L Standard Error 2.19
Change From Baseline To Month 24 Of Aspartate Aminotransferase (AST) Month 12	-11.8 U/L Standard Error 2.36	-5.4 U/L Standard Error 2.27
Change From Baseline To Month 24 Of Aspartate Aminotransferase (AST) Month 24	-14.8 U/L Standard Error 2.78	-6.0 U/L Standard Error 2.72

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Alanine Aminotransferase (ALT) Month 6	-24.3 U/L Standard Error 2.62	-7.4 U/L Standard Error 2.59
Change From Baseline To Month 24 Of Alanine Aminotransferase (ALT) Month 12	-20.5 U/L Standard Error 3.49	-12.8 U/L Standard Error 3.37
Change From Baseline To Month 24 Of Alanine Aminotransferase (ALT) Month 24	-28.5 U/L Standard Error 2.92	-19.4 U/L Standard Error 2.87

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Alkaline Phosphatase (ALP) Month 6	-134.3 U/L Standard Error 10.86	-37.4 U/L Standard Error 10.85
Change From Baseline To Month 24 Of Alkaline Phosphatase (ALP) Month 12	-144.8 U/L Standard Error 12.05	-68.8 U/L Standard Error 11.72
Change From Baseline To Month 24 Of Alkaline Phosphatase (ALP) Month 24	-156.4 U/L Standard Error 14.93	-113.1 U/L Standard Error 14.60

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Gamma-glutamyl Transferase (GGT) Month 6	-155.5 U/L Standard Error 15.04	-47.0 U/L Standard Error 14.99
Change From Baseline To Month 24 Of Gamma-glutamyl Transferase (GGT) Month 12	-152.2 U/L Standard Error 18.24	-63.4 U/L Standard Error 17.71
Change From Baseline To Month 24 Of Gamma-glutamyl Transferase (GGT) Month 24	-175.6 U/L Standard Error 22.49	-127.7 U/L Standard Error 22.04

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of Albumin Month 6	-0.4 g/L Standard Error 0.19	-0.1 g/L Standard Error 0.19
Change From Baseline To Month 24 Of Albumin Month 12	-0.3 g/L Standard Error 0.23	-0.3 g/L Standard Error 0.22
Change From Baseline To Month 24 Of Albumin Month 24	-0.1 g/L Standard Error 0.29	-1.1 g/L Standard Error 0.28

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 24 Of INR Month 6	0.02 ratio Standard Error 0.014	0.02 ratio Standard Error 0.014
Change From Baseline To Month 24 Of INR Month 12	0.01 ratio Standard Error 0.009	0.02 ratio Standard Error 0.008
Change From Baseline To Month 24 Of INR Month 24	0.03 ratio Standard Error 0.014	0.06 ratio Standard Error 0.014

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of MELD Score Month 12	0 score on a scale Interval -0.6 to 0.6	0 score on a scale Interval -0.5 to 1.3
Change From Baseline To Month 72 Of MELD Score Month 24	0 score on a scale Interval -1.0 to 0.7	0.20 score on a scale Interval -0.5 to 1.7
Change From Baseline To Month 72 Of MELD Score Month 36	0 score on a scale Interval -1.0 to 0.5	0.60 score on a scale Interval -0.5 to 2.9
Change From Baseline To Month 72 Of MELD Score Month 48	0 score on a scale Interval -0.95 to 1.45	0.40 score on a scale Interval -0.8 to 1.6
Change From Baseline To Month 72 Of MELD Score Month 60	0 score on a scale Interval -1.3 to 0.4	0 score on a scale Interval -1.2 to 1.85
Change From Baseline To Month 72 Of MELD Score Month 72	0 score on a scale Interval -1.2 to 5.2	1.95 score on a scale Interval -1.4 to 3.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of MELD-Na Score Month 12	0 score on a scale Interval -1.0 to 1.0	0 score on a scale Interval -1.0 to 1.0
Change From Baseline To Month 72 Of MELD-Na Score Month 24	0 score on a scale Interval -2.0 to 0.0	0 score on a scale Interval -1.0 to 1.0
Change From Baseline To Month 72 Of MELD-Na Score Month 36	0 score on a scale Interval -2.0 to 0.0	0 score on a scale Interval -1.0 to 2.0
Change From Baseline To Month 72 Of MELD-Na Score Month 48	0 score on a scale Interval -2.0 to 2.0	0 score on a scale Interval -2.0 to 2.0
Change From Baseline To Month 72 Of MELD-Na Score Month 60	-1.0 score on a scale Interval -3.0 to 0.0	0 score on a scale Interval -2.5 to 1.5
Change From Baseline To Month 72 Of MELD-Na Score Month 72	0 score on a scale Interval -2.0 to 0.0	0.5 score on a scale Interval -3.5 to 1.5

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of CPS Month 36	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0
Change From Baseline To Month 72 Of CPS Month 48	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0
Change From Baseline To Month 72 Of CPS Month 60	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0
Change From Baseline To Month 72 Of CPS Month 72	0 score on a scale Interval 0.0 to 2.0	1.0 score on a scale Interval 0.0 to 1.0
Change From Baseline To Month 72 Of CPS Month 12	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0
Change From Baseline To Month 72 Of CPS Month 24	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 12	0 score on a scale Interval -0.38 to 0.32	0.080 score on a scale Interval -0.205 to 0.535
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 24	-0.080 score on a scale Interval -0.27 to 0.39	0.140 score on a scale Interval -0.17 to 0.66
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 36	-0.040 score on a scale Interval -0.41 to 0.28	0.050 score on a scale Interval -0.24 to 0.65
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 48	0.030 score on a scale Interval -0.43 to 0.62	0.210 score on a scale Interval -0.24 to 0.81
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 60	-0.145 score on a scale Interval -0.575 to 0.16	-0.060 score on a scale Interval -0.49 to 0.79
Change From Baseline To Month 72 Of Mayo Risk Score (MRS) Month 72	-0.130 score on a scale Interval -0.46 to 0.32	0.990 score on a scale Interval 0.24 to 1.165

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 12	-0.305 g/L Interval -0.955 to 0.025	-0.160 g/L Interval -0.72 to 0.2
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 24	-0.470 g/L Interval -1.25 to -0.09	-0.230 g/L Interval -0.63 to 0.17
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 36	-0.700 g/L Interval -1.44 to -0.025	-0.330 g/L Interval -1.27 to 0.0
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 48	-0.525 g/L Interval -1.615 to 0.005	-0.690 g/L Interval -1.54 to 0.09
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 60	-0.745 g/L Interval -1.545 to -0.075	-0.350 g/L Interval -1.05 to -0.15
Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) Month 72	-1.590 g/L Interval -4.1 to 0.05	-0.640 g/L Interval -1.06 to 0.645

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 12	-0.140 mg/L Interval -1.32 to 1.36	0.400 mg/L Interval -0.76 to 2.72
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 24	-0.280 mg/L Interval -1.21 to 1.11	0.290 mg/L Interval -1.45 to 2.95
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 36	-0.525 mg/L Interval -2.16 to 0.63	0.340 mg/L Interval -1.46 to 3.83
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 48	-0.260 mg/L Interval -1.7 to 2.18	-0.180 mg/L Interval -1.2 to 2.025
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 60	-0.720 mg/L Interval -3.02 to 0.74	-0.730 mg/L Interval -2.7 to 1.65
Change From Baseline To Month 72 Of C-reactive Protein (CRP) Month 72	-0.100 mg/L Interval -2.74 to 2.57	0.765 mg/L Interval -2.63 to 4.715

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 12	0 pg/mL Interval -0.362 to 0.58	0.058 pg/mL Interval -0.236 to 0.791
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 24	0.203 pg/mL Interval -0.213 to 0.758	0.323 pg/mL Interval -0.039 to 0.654
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 36	0.055 pg/mL Interval -0.304 to 0.627	0.296 pg/mL Interval -0.078 to 0.75
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 48	0.165 pg/mL Interval -0.195 to 0.814	0.539 pg/mL Interval 0.113 to 0.918
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 60	-0.009 pg/mL Interval -0.765 to 0.596	0.419 pg/mL Interval -0.153 to 0.753
Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) Month 72	0.046 pg/mL Interval -0.39 to 0.175	0.616 pg/mL Interval -1.318 to 0.788

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 12	73.50 pg/mL Interval 2.85 to 208.0	-2.80 pg/mL Interval -57.65 to 36.5
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 24	72.00 pg/mL Interval 1.0 to 211.0	-0.40 pg/mL Interval -63.0 to 61.4
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 36	39.90 pg/mL Interval -17.7 to 132.0	-2.00 pg/mL Interval -51.0 to 50.8
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 48	56.00 pg/mL Interval -24.0 to 219.0	-9.45 pg/mL Interval -59.9 to 39.3
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 60	14.40 pg/mL Interval -30.0 to 183.0	-1.45 pg/mL Interval -83.4 to 156.0
Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) Month 72	-106.90 pg/mL Interval -172.3 to -1.0	-62.00 pg/mL Interval -239.0 to -26.5

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 12	-34.450 U/L Interval -138.01 to 45.8	9.100 U/L Interval -78.54 to 123.77
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 24	-57.660 U/L Interval -158.96 to 8.47	17.545 U/L Interval -54.63 to 165.835
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 36	-45.935 U/L Interval -171.225 to 18.715	6.680 U/L Interval -112.01 to 76.11
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 48	-81.035 U/L Interval -158.9 to 33.55	0.290 U/L Interval -130.71 to 79.41
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 60	-117.660 U/L Interval -232.77 to 0.0	-56.390 U/L Interval -159.78 to 77.02
Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) Month 72	-182.590 U/L Interval -207.02 to 17.06	-32.745 U/L Interval -199.555 to 78.07

SECONDARY outcome

Timeframe: 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 C4, were assessed.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 12	-2.222 ng/mL Interval -8.11 to 0.002	-0.250 ng/mL Interval -2.691 to 1.523
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 24	-3.700 ng/mL Interval -10.119 to -0.885	-0.861 ng/mL Interval -5.5 to 0.9
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 36	-3.826 ng/mL Interval -9.38 to 0.182	-1.225 ng/mL Interval -5.62 to 1.161
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 48	-4.220 ng/mL Interval -9.87 to 0.0	-1.168 ng/mL Interval -12.24 to 1.691
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 60	-3.250 ng/mL Interval -10.334 to -0.11	-1.161 ng/mL Interval -9.591 to 0.66
Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) Month 72	-7.500 ng/mL Interval -10.914 to -0.69	-0.947 ng/mL Interval -15.281 to -0.277

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 12	0.10 score on a scale Interval -0.5 to 0.6	0.10 score on a scale Interval -0.2 to 0.7
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 24	0 score on a scale Interval -0.7 to 0.6	0.20 score on a scale Interval -0.4 to 1.0
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 36	-0.20 score on a scale Interval -0.9 to 0.7	0 score on a scale Interval -0.6 to 0.7
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 48	0.25 score on a scale Interval -0.45 to 0.8	0.10 score on a scale Interval -0.7 to 1.1
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 60	-0.20 score on a scale Interval -1.2 to 0.6	0.10 score on a scale Interval -1.0 to 1.0
Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) Month 72	0 score on a scale Interval -0.8 to 2.8	-0.20 score on a scale Interval -1.1 to 0.45

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 12	0.25 kPa Interval -2.4 to 4.05	0.90 kPa Interval -1.8 to 7.3
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 24	-0.60 kPa Interval -2.6 to 3.6	1.50 kPa Interval -2.2 to 15.6
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 36	0.30 kPa Interval -3.4 to 5.5	2.00 kPa Interval -1.6 to 9.1
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 48	0.70 kPa Interval -2.2 to 4.0	1.00 kPa Interval -2.8 to 11.9
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 60	0.20 kPa Interval -2.5 to 6.0	-1.35 kPa Interval -4.7 to 1.9
Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography Month 72	-2.40 kPa Interval -2.5 to 2.7	3.20 kPa Interval -2.2 to 8.7

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=168 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo n=166 Participants Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	162 participants	158 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	53 participants	53 participants

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Obeticholic Acid n=149 Participants Participants received OCA 5 mg for a minimum of 3 months and titrating up to 10 mg for the remainder of the study (based on tolerability and CP Score). Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily, titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, titrating up to a maximum dose and frequency of 10 mg twice weekly based on tolerability and biochemical response for the duration of the study.	Placebo Participants received one tablet daily (or a lower frequency depending on CP score) for the remainder of the study.
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 3)	119 ng/mL Geometric Coefficient of Variation 185	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 6)	102 ng/mL Geometric Coefficient of Variation 186	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 9)	175 ng/mL Geometric Coefficient of Variation 33.0	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 12)	117 ng/mL Geometric Coefficient of Variation 153	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 24)	113 ng/mL Geometric Coefficient of Variation 121	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 36)	84.5 ng/mL Geometric Coefficient of Variation 169	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 48)	203 ng/mL Geometric Coefficient of Variation 181	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QD (Month 60)	7.96 ng/mL Geometric Coefficient of Variation 173	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 3)	123 ng/mL Geometric Coefficient of Variation 191	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 6)	103 ng/mL Geometric Coefficient of Variation 232	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 9)	396 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 12)	103 ng/mL Geometric Coefficient of Variation 97.2	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 24)	134 ng/mL Geometric Coefficient of Variation 17.1	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QOD (Month 48)	307 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 3)	57.3 ng/mL Geometric Coefficient of Variation 199	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 6)	31.0 ng/mL Geometric Coefficient of Variation 125	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 12)	73.5 ng/mL Geometric Coefficient of Variation 302	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 24)	171 ng/mL Geometric Coefficient of Variation 109	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 36)	245 ng/mL Geometric Coefficient of Variation 34.8	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg QW (Month 48)	141 ng/mL Geometric Coefficient of Variation 216	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 3)	61.9 ng/mL Geometric Coefficient of Variation 54.7	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 6)	108 ng/mL Geometric Coefficient of Variation 57.1	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 12)	187 ng/mL Geometric Coefficient of Variation 30.8	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 24)	208 ng/mL Geometric Coefficient of Variation 61.0	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 36)	225 ng/mL Geometric Coefficient of Variation 159	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 48)	502 ng/mL Geometric Coefficient of Variation 59.6	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg Q2W (Month 60)	7.32 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg other regimens (Month 3)	50.3 ng/mL Geometric Coefficient of Variation 1730	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg other regimens (Month 6)	79.6 ng/mL Geometric Coefficient of Variation 68.2	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg other regimens (Month 12)	20.6 ng/mL Geometric Coefficient of Variation 500	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 5 mg other regimens (Month 24)	91.1 ng/mL Geometric Coefficient of Variation 236	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 6)	126 ng/mL Geometric Coefficient of Variation 161	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 9)	51.1 ng/mL Geometric Coefficient of Variation 167	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 12)	86.9 ng/mL Geometric Coefficient of Variation 188	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 24)	85.6 ng/mL Geometric Coefficient of Variation 152	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 36)	79.9 ng/mL Geometric Coefficient of Variation 143	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 48)	81.2 ng/mL Geometric Coefficient of Variation 161	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QD (Month 60)	48.6 ng/mL Geometric Coefficient of Variation 323	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QOD (Month 12)	102 ng/mL Geometric Coefficient of Variation 576	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QOD (Month 24)	25.5 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg QOD (Month 48)	9.08 ng/mL Geometric Coefficient of Variation NA No data on OCA concentration was detected.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 6)	538 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 9)	566 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 12)	41.7 ng/mL Geometric Coefficient of Variation 45.6	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 24)	62.5 ng/mL Geometric Coefficient of Variation 35.9	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 36)	96.3 ng/mL Geometric Coefficient of Variation 132	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 48)	70.9 ng/mL Geometric Coefficient of Variation 218	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q2W (Month 60)	83.8 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—
Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen 10 mg Q3D (Month 12)	0.861 ng/mL Geometric Coefficient of Variation NA No variation was calculated.	—

SECONDARY outcome

Timeframe: 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, 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.