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

Study Overview
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Brief Summary
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Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC participants.

Detailed Description
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This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 428 participants with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of participants; dose and frequency will be modified for participants with cirrhosis and classified as Child-Pugh (CP) B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as CP A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as CP A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years. Participants are expected to have a minimum follow-up time of approximately 6 years.

Official Title
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A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Patients With Primary Biliary Cholangitis

Conditions
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Liver Cirrhosis, Biliary

Intervention / Treatment
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* Drug: Obeticholic Acid (OCA)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors: History of elevated Alkaline phosphatase levels for at least 6 months Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]) Liver biopsy consistent with PBC A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0 Exclusion Criteria: History or presence of other concomitant liver diseases including: Hepatitis C virus infection Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor Primary sclerosing cholangitis (PSC) Alcoholic liver disease Definite autoimmune liver disease or overlap hepatitis Nonalcoholic steatohepatitis (NASH) Gilbert's Syndrome Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria Cirrhosis with complications, including history (within the past 12 months) or presence of: Variceal bleed Uncontrolled ascites Encephalopathy Spontaneous bacterial peritonitis Known or suspected HCC Prior transjugular intrahepatic portosystemic shunt procedure Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine >2 mg/dL (178 μmol/L) Mean total bilirubin >5x ULN Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions) If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating Known history of human immunodeficiency virus infection Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months) Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study History of alcohol abuse or other substance abuse within 1 year prior to Day 0 Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain History of known or suspected clinically significant hypersensitivity to OCA or any of its components UDCA naïve (unless contraindicated)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obeticholic Acid (OCA) 5 mg to 10 mg<br>Obeticholic Acid (OCA) 5 mg for a minimum 3 months and then titrating up to a maximum 10 mg for the remainder of the trial (based on tolerability and CP Score). | Drug: Obeticholic Acid (OCA)<br>* 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, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study.<br>* Other names: INT-747;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* One tablet daily (or a lower frequency depending on CP score) for the remainder of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the First Occurrence of Composite Endpoint | 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 to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years) | 
| Time to the First Occurrence of Primary Clinical Event (Expanded Endpoint) | 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 to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To First Occurrence Of Severe Decompensating Events of Expanded Composite Endpoint | 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 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) | 
| Time To Liver Transplant Or Death (All-cause) | 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 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) | 
| Time to First Occurrence of Fatal Event (All-Cause) | 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 to first occurrence from date of randomization until the date of death from any cause (up to 7 years) | 
| Time to First Occurrence of Liver Transplant | 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 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) | 
| Time to First Occurrence of Hospitalization Due to Hepatic Events | 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 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) | 
| Time to First Occurrence of Uncontrolled or Refractory Ascites | 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 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) | 
| Time to First Occurrence of MELD Score ≥15 | 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 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) | 
| Time To Development Of Varix/Varices | 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 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) | 
| Time To Liver-Related Death | 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 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) | 
| Time To Liver-Related Death Or Liver Transplant | 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 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) | 
| Time To Liver-Related Death, Liver Transplant, Or MELD Score ≥15 | 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 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) | 
| Progression To Cirrhosis (for Noncirrhotic Subjects at Baseline) | 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 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) | 
| Time To Occurrence Of Hepatocellular Carcinoma (HCC) | 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 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) | 
| Change From Baseline To Month 24 Of Total Bilirubin | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Direct Bilirubin | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Aspartate Aminotransferase (AST) | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Alanine Aminotransferase (ALT) | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Alkaline Phosphatase (ALP) | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Gamma-glutamyl Transferase (GGT) | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of Albumin | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 24 Of INR | 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. | Baseline up to Month 24 | 
| Change From Baseline To Month 72 Of MELD Score | 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. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of MELD-Na Score | 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. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of CPS | 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). | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Mayo Risk Score (MRS) | 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. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Immunoglobulin-M (IgM) | Markers of inflammation, which include IgM, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of C-reactive Protein (CRP) | Markers of inflammation, which include CRP, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Tumor Necrosis Factor-α (TNF-α) | Markers of inflammation, which include TNF-α, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Fibroblast Growth Factor-19 (FGF-19) | Markers of hepatic fibrosis, which include FGF-19, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Cytokeratin-18 (CK-18) | Markers of inflammation, which include CK-18, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of 7α-hydroxy-4-cholesten-3-one (C4) | Markers of hepatic fibrosis, which include C4, were assessed. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Enhanced Liver Fibrosis (ELF) | 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. | Baseline up to Month 72 | 
| Change From Baseline To Month 72 Of Liver Stiffness - Transient Elastography | Hepatic stiffness was measured using non-invasive transient Elastography with Fibroscan® TE device. | Baseline up to Month 72 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to the last IP dose plus 30 days and prior to commercial OCA initiation date (up to 7 years) | 
| Pharmacokinetic (PK) Population: Fasting Trough Concentrations Of OCA By Dose Regimen | The fasting trough PK concentrations of OCA of different dose regimens taken throughout the study are reported. | Months 3, 6, 9, 12, 24, 36, 48, and 60 | 
| PK Population: Serial Concentration of OCA By Dose Regimen | 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. | Month 9 | 
| PK Population: Area Under The Concentration-Time Curve (AUC) From 0 to 6 Hours Post-dose (AUC0-6h) Of Participants Who Received 5 mg QD OCA and With CP Score=Non-Cirrhotic (NC) | 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. | Month 9 | 
| PK Population: AUC From 0 to 24 Hours Post-dose (AUC0-24h) Of Participants Who Received 5 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Maximum Observed Concentration (Cmax) Of Participants Who Received 5mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Time to Cmax (Tmax) Of Participants Who Received 5mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Metabolite to Parent Ratio of AUC0-6h (MRAUC) Of Participants Who Received 5mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Metabolite to Parent Ratio of Cmax (MRCmax) Of Participants Who Received 5mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 5 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 5 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 5mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 5mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: Concentration at 24 Hours Post-dose (Ctrough) Of Participants Who Received 5mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 5mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 5mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 5mg QD OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 5 mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 5 mg QOD OCA and With CP Score=NC | 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 | Month 9 | 
| PK Population: Cmax Of Participants Who Received 5mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 5mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 5mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 5mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 5mg QOD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg QD OCA and With CP Score=NC | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg QD OCA and With CPS Score=A | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg QD OCA and With CPS Score=A | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg QD OCA and With CP Score=A | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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 | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg Q2W OCA and With CP Score=B | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 5 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 5 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 5 mg QOD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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 | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg QD OCA and With MELD Category=A | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg QD OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: AUC0-6h Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: AUC0-24h Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Cmax Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Tmax Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Ctrough Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRAUC Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: MRCmax Of Participants Who Received 10 mg Q2W OCA and With MELD Category=B | 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. | Month 9 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 5 mg QD OCA | The trough concentration of OCA in the cirrhotic participants who received 5 mg QD OCA was reported. | Months 3, 6, 12, 24, and 48 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 5 mg QD OCA | The trough concentration of OCA in the non-cirrhotic participants who received 5 mg QD OCA was reported. | Months 3, 6, 9, 12, and 24 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 5 mg QOD OCA | The trough concentration of OCA in the cirrhotic participants who received 5 mg QOD OCA was reported. | Months 6, 12, and 24 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 5 mg QOD OCA | The trough concentration of OCA in the non-cirrhotic participants who received 5 mg QOD OCA was reported. | Months 3, 6, and 12 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 5 mg QW OCA | The trough concentration of OCA in the cirrhotic participants who received 5 mg QW OCA was reported. | Months 6 and 12 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 5 mg QW OCA | In Month 12, the trough concentration of OCA in the non-cirrhotic participants who received 5 QW QOD OCA was reported. | Month 12 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 5 mg Q2W OCA | The trough concentration of OCA in the cirrhotic participants who received 5 mg Q2W OCA was reported. | Months 6, 24, 36 and 48 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 5 mg Q2W OCA | The trough concentration of OCA in the non-cirrhotic participants who received 5 Q2W QOD OCA was reported. | Months 3, 6, 12, 24, 36, and 48 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 10 mg QD OCA | The trough concentration of OCA in the cirrhotic participants who received 10 mg QD OCA was reported. | Months 6, 9, 12, 24, 36, and 60 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 10 mg QD OCA | The trough concentration of OCA in the non-cirrhotic participants who received 10 QD QOD OCA was reported. | Months 6, 9, 12, 24, and 36 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 10 mg QOD OCA |  | Months 3, 6, 9, 12, 24, 36, 48, and 60 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 10 mg QOD OCA | In Month 12, the trough concentration of OCA in the non-cirrhotic participants who received 10 mg QOD OCA was reported. | Month 12 | 
| PK Population: Trough Concentrations Of Cirrhotic Participants Who Received 10 mg Q2W OCA | In Month 6, the trough concentration of OCA in the cirrhotic participants who received 10 mg Q2W OCA was reported. | Month 6 | 
| PK Population: Trough Concentrations Of Non-Cirrhotic Participants Who Received 10 mg Q2W OCA | In Month 6, the trough concentration of OCA in the non-cirrhotic participants who received 10 mg Q2W OCA was reported. | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Biliary Cirrhosis, PBC, Cirrhosis, Liver