MedPath

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

Phase 4
Terminated
Conditions
Liver Cirrhosis, Biliary
Interventions
Drug: Obeticholic Acid (OCA)
Drug: Placebo
Registration Number
NCT03633227
Lead Sponsor
Intercept Pharmaceuticals
Brief Summary

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

Detailed Description

Not available

Recruitment & Eligibility

Status
TERMINATED
Sex
All
Target Recruitment
22
Inclusion Criteria

  1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, defined as having ≥2 of the following 3 diagnostic factors:

    • History of elevated alkaline phosphatase (ALP) levels for at least 6 months
    • Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), PBC specific antibodies (anti-glycoprotein 210 [GP210] and/or anti-SP100) and/or antibodies against the major M2 components (E2 component of mitochondrial pyruvate dehydrogenase complex [PDC-E2], 2-oxo-glutaric acid dehydrogenase complex)
    • Liver biopsy consistent with PBC (collected at any time prior to Screening)

  2. Evidence of cirrhosis including at least one of the following:

    • Biopsy results consistent with PBC Stage 4

    • Liver stiffness as assessed by Transient Elastography (TE) Median Value ≥16.9 kilopascals (kPa)

    • Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement of portal vein and splenomegaly)

    • Combined low platelet count (<140,000/cubic millimeter [mm^3]) with

      • persistent decrease in serum albumin, or
      • elevation in prothrombin time/international normalized ratio (INR) (not due to antithrombotic agent use), or
      • elevated bilirubin (2*upper limit of normal [ULN])

  3. Satisfy the criteria of the modified Child-Pugh (CP) classification for hepatic impairment during Screening:

    • Moderate: CP-B (Scores 7 to 9) or
    • Severe: CP-C (Scores 10 to 12)

  4. Model of end-stage liver disease (MELD) score of 6 to 24 at Screening

  5. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months)

Exclusion Criteria

  1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6)

  2. History of liver transplant or organ transplant

  3. History of alcohol or drug abuse within 12 months prior to Screening

  4. Hepatic encephalopathy (as defined by a West Haven score of ≥2

  5. History or presence of other concomitant liver diseases including:

    • Hepatitis C virus infection and ribonucleic acid (RNA) positive
    • Active hepatitis B infection; however, participants who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
    • Primary sclerosing cholangitis
    • Alcoholic liver disease
    • Definite autoimmune liver disease or overlap hepatitis
    • Gilbert's Syndrome

  6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization

Other inclusion/exclusion criteria may apply.

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Obeticholic Acid (OCA)Obeticholic Acid (OCA)Participants will initiate treatment with OCA 5 milligrams (mg) tablets orally once weekly. At Week 12, if there are no safety concerns, the dose will be up-titrated to OCA 5 mg twice weekly. Every 6 weeks thereafter, based on tolerability assessments, further up-titration of dose will be considered. At each titration visit, the participants will start the higher dose regimen no earlier than 2 days after the prior dose. The maximum dose titration will be OCA 10 mg twice weekly at least 3 days apart. The minimum treatment duration will be 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).
PlaceboPlaceboParticipants will receive OCA matching placebo orally once weekly or twice weekly for the duration of at least 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).
Primary Outcome Measures
NameTimeMethod
Tmax of Total OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Tmax of Unconjugated OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
AUC0-24h of Unconjugated OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

Ctrough of Unconjugated OCA at Week 2424 hours post-dose at Week 24

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

Cmax of Unconjugated OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
Maximum Observed Concentration (Cmax) of Total OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

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

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

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

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

Ctrough of Unconjugated OCA at Week 1224 hours post-dose at Week 12

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

Cmax of Unconjugated OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
Tmax of Unconjugated OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
AUC0-24h of Unconjugated OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

AUC0-24h of Unconjugated OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

Trough Concentration (Ctrough) of Total OCA at Week 1224 hours post-dose at Week 12

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

Time to Maximum Concentration (Tmax) of Total OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Area Under the Concentration Versus Time Curve From Zero Time to 24 Hours (AUC0-24h) of Total OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

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

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

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

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

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

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

Ctrough of Total OCA at Week 2424 hours post-dose at Week 24

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

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

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

AUC0-24h of Total OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

Ctrough of Total OCA at Week 1824 hours post-dose at Week 18

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

AUC0-24h of Total OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

AUC0-24h of Total OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Ctrough of Total OCA at Week 3024 hours post-dose at Week 30

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

Tmax of Unconjugated OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
AUC0-24h of Glyco-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Tmax of Glyco-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
MRCmax of Glyco-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

Ctrough of Glyco-OCA at Week 3024 hours post-dose at Week 30

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

Tmax of Glyco-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Cmax of Total OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

Ctrough of Total OCA at Week 4824 hours post-dose at Week 48

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

AUC0-24h of Total OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

Cmax of Unconjugated OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
Ctrough of Unconjugated OCA at Week 1824 hours post-dose at Week 18

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

AUC0-24h of Unconjugated OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Ctrough of Unconjugated OCA at Week 3024 hours post-dose at Week 30

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

Cmax of Unconjugated OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Ctrough of Unconjugated OCA at Week 4824 hours post-dose at Week 48

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

AUC0-24h of Unconjugated OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Tmax of Unconjugated OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
Tmax of Unconjugated OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Metabolite to Parent Ratio of Cmax (MRCmax) of Glyco-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Ctrough of Glyco-OCA at Week 1824 hours post-dose at Week 18

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

Cmax of Glyco-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
AUC0-24h of Glyco-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

Cmax of Glyco Conjugate of OCA (Glyco-OCA) at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
Metabolite to Parent Ratio of AUC-0-24h (MRAUC) of Glyco-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Cmax of Glyco-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
Tmax of Glyco-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
Ctrough of Glyco-OCA at Week 1224 hours post-dose at Week 12

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

AUC0-24h of Glyco-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

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

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

Tmax of Glyco-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
MRAUC of Glyco-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Cmax of Glyco-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
Ctrough of Glyco-OCA at Week 2424 hours post-dose at Week 24

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

AUC0-24h of Glyco-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

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

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

Tmax of Glyco-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
AUC0-24h of Tauro-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

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

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

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

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

Tmax of Tauro-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
Ctrough of Tauro-OCA at Week 1824 hours post-dose at Week 18

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

Tmax of Tauro-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
Ctrough of Tauro-OCA at Week 2424 hours post-dose at Week 24

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

AUC0-24h of Tauro-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Cmax of Tauro-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
AUC0-24h of Tauro-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

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

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

Cmax of Glucuronide Metabolite of OCA (OCA-glucuronide) at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
MRAUC of Glyco-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

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

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

Ctrough of Glyco-OCA at Week 4824 hours post-dose at Week 48

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

Cmax of Tauro-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
Cmax of Glyco-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Cmax of Tauro Conjugate of OCA (Tauro-OCA) at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
AUC0-24h of Tauro-OCA at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

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

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

Tmax of Tauro-OCA at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
Ctrough of Tauro-OCA at Week 1224 hours post-dose at Week 12

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

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

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

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

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

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

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

Tmax of Tauro-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
AUC0-24h of Tauro-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

AUC0-24h of Glyco-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

Cmax of Tauro-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Cmax of Tauro-OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
MRCmax of Tauro-OCA at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

Tmax of Tauro-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Ctrough of OCA-glucuronide at Week 1224 hours post-dose at Week 12

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

AUC0-24h of OCA-glucuronide at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

Ctrough of OCA-glucuronide at Week 1824 hours post-dose at Week 18

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

Cmax of OCA-glucuronide at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
Ctrough of Tauro-OCA at Week 3024 hours post-dose at Week 30

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

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

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

Ctrough of Tauro-OCA at Week 4824 hours post-dose at Week 48

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

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

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

Tmax of OCA-glucuronide at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12
MRAUC of OCA-glucuronide at Week 12Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12

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

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

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

Cmax of OCA-glucuronide at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
MRCmax of OCA-glucuronide at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

Tmax of OCA-glucuronide at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18
AUC0-24h of OCA-glucuronide at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

Tmax of OCA-glucuronide at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
Ctrough of OCA-glucuronide at Week 2424 hours post-dose at Week 24

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

AUC0-24h of OCA-glucuronide at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24

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

Tmax of OCA-glucuronide at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
MRAUC of OCA-glucuronide at Week 18Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18

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

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

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

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

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

Cmax of OCA-glucuronide at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30
Ctrough of OCA-glucuronide at Week 3024 hours post-dose at Week 30

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

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

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

Cmax of OCA-glucuronide at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Ctrough of OCA-glucuronide at Week 4824 hours post-dose at Week 48

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

AUC0-24h of OCA-glucuronide at Week 30Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30

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

AUC0-24h of OCA-glucuronide at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

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

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

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

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

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

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

Tmax of OCA-glucuronide at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)Baseline up to approximately 3 years

An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug.

An SAE was any AE that results in death, was life-threatening, resulted in a persistent or significant disability/incapacity, resulted in in-patient hospitalization or prolonged an existing hospitalization, was a congenital anomaly/birth defect, or was an important medical event that could jeopardize the participant or could have required medical intervention to prevent one of the outcomes listed above.

TEAE was defined as any AE if it met one or more of the following criteria: 1) An AE started on or after the first study drug dose and within 30 days after the last dose of study drug, 2) An AE occurred prior to the first study drug dose that worsens (increase in grade) after the first study drug dose.

Cmax of Unconjugated OCA at Week 24Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24
MRAUC of Glyco-OCA at Week 48Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48

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

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

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

Secondary Outcome Measures
NameTimeMethod
Number of Participants by Child-Pugh Score Component Category (Ascites Categories)Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of participants with Child-Pugh component - ascites categories of none, mild, and moderate-severe has been reported. The ascites categories were defined per investigator's discretion.

Change From Baseline in Aspartate Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Total Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3

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

Change From Baseline in Fibroblast Growth Factor-19 (FGF-19) Concentrations at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3
Change From Baseline in the Model of End-stage Liver Disease (MELD) Score at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

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

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

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

Number of Participants by Child-Pugh Score Component Category (Prothrombin Time Categories)Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of participants with Child-Pugh component - prothrombin time (measured as INR) in categories of \<1.7, 1.7 - 2.3, and \>2.3 has been reported.

Number of Participants by Child-Pugh Score Component Category (Serum Albumin Categories)Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of participants with Child-Pugh component - serum albumin levels in categories of \>35 gram per liter (g/L), 28-35 g/L, or \<28 g/L has been reported.

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

The MELD-Na scoring system is used to assess the severity of chronic liver disease in the participants with an initial MELD(i) score greater than 11. MELD-Na score is derived from the participant's serum total bilirubin, serum creatinine, INR, and sodium. The MELD-Na score is re-calculated as follows:

MELD-Na = MELD(i) + 1.32\*(137-Na) - \[0.033\*MELD(i)\*(137-Na)\]. MELD score ranges from 6-40 with higher scores indicating more severe liver disease and a worse outcome.

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

Number of Participants by Child-Pugh Score Component Category (Total Bilirubin Categories)Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of participants with Child-Pugh component - total bilirubin levels in categories of \<34 micromole per liter (µmol/L), 34-50 µmol/L, and \>50 µmol/L has been reported.

Number of Participants by Child-Pugh Score Component Category (Hepatic Encephalopathy Categories)Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15

Number of participants with Child-Pugh component - Hepatic encephalopathy in categories of Grade 0, Grade 1 or 2, and Grade 3 and 4 has been reported.

Grade 0: normal consciousness, normal personality, normal neurological examination, normal electroencephalogram.

Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles, per second (cps) waves.

Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.

Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.

Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.

Change From Baseline in Total Bilirubin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Direct Bilirubin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Alkaline Phosphatase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Platelets at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Total Endogenous Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3

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

Change From Baseline in 7α-hydroxy-4-cholesten-3-one (C4) at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3
Change From Baseline in Alanine Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Gamma Glutamyl Transferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Prothrombin INR at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Creatinine at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15
Change From Baseline in Albumin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15

Trial Locations

Locations (39)

The Ohio State University Wexner Medical Center

🇺🇸

Columbus, Ohio, United States

Mercy Medical Center

🇺🇸

Baltimore, Maryland, United States

Hospital Britanico de Buenos Aires

🇦🇷

Caba, Argentina

Hospital Italiano de Buenos Aires

🇦🇷

Buenos Aires, Argentina

Hospital Universitario Austral

🇦🇷

Pilar, Argentina

Higea S.A.

🇦🇷

Mendoza, Argentina

Royal Prince Alfred Hospital

🇦🇺

Camperdown, Australia

Nepean Hospital

🇦🇺

Kingswood, Australia

CUB Hospital Erasme

🇧🇪

Brussels, Belgium

University Hospital Leuven

🇧🇪

Leuven, Belgium

Universitair Ziekenhuis Antwerpen UZA

🇧🇪

Edegem, Belgium

Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo

🇧🇷

São Paulo, Brazil

Toronto General Hospital

🇨🇦

Toronto, Canada

West Tallinn Central Hospital

🇪🇪

Tallinn, Estonia

Tartu University Hospital

🇪🇪

Tartu, Estonia

Universitatsklinikum Leipzig AoR

🇩🇪

Leipzig, Germany

AOU Ospedale Civile S. Agostino Estense - UO Medicina Metabolica

🇮🇹

Modena, Italy

Azienda Socio Sanitaria Territoriale (ASST) di Monza

🇮🇹

Monza, MB, Italy

Hospital of Lithuanian University of Health Sciences Kauno Klinikos

🇱🇹

Kaunas, Lithuania

Klaipeda Seamen's Hospital

🇱🇹

Klaipeda, Lithuania

Hospital Universitari I Politecnic La Fe de Valencia

🇪🇸

Valencia, Spain

Paseo Vall d'Hebron

🇪🇸

Barcelona, Spain

Hospital Universitario Virgen del Rocio

🇪🇸

Sevilla, Spain

Schiff Center for Liver Diseases/ University of Miami

🇺🇸

Miami, Florida, United States

University Of Michigan

🇺🇸

Ann Arbor, Michigan, United States

Hospital Provincial del Centenario

🇦🇷

Rosario, Argentina

Hospital de Clinicas de Porto Alegre

🇧🇷

Rio Grande, Brazil

Bekes Megyei Kozponti Korhaz Dr. Rethy Pal Tagkorhaz, 4. Belgyogyaszat-Gasztroenterologia-Hepatologia

🇭🇺

Bekescsaba, Hungary

Hospital de Gastroenterologia "Dr Carlos Bonorino Udaondo"

🇦🇷

Ciudad Autonoma de Buenos Aire, Argentina

Hospital das Clínicas da Universidade Federal de Minas Gerais - UFMG

🇧🇷

Belo Horizonte, Brazil

Vilnius University Hospital Santaros Klinikos

🇱🇹

Vilnius, Lithuania

Hospital Aleman

🇦🇷

Caba, Argentina

Inland Empire Liver Foundation

🇺🇸

Rialto, California, United States

University of California, Ddavis Medical Center

🇺🇸

Sacramento, California, United States

Kansas City Research Institute

🇺🇸

Kansas City, Missouri, United States

The Liver Institute at Methodist Dallas Medical Center

🇺🇸

Dallas, Texas, United States

UPMC Center for Liver Diseases

🇺🇸

Pittsburgh, Pennsylvania, United States

Baylor College of Medicine- Advanced Liver Therapies

🇺🇸

Houston, Texas, United States

American Research Corporation at theTexas Liver Institute

🇺🇸

San Antonio, Texas, United States

Related Trials

Related News

FDA Rejects Full Approval of Ocaliva for Second-Line PBC Treatment

• The FDA has denied full approval for Intercept Pharmaceuticals' Ocaliva (obeticholic acid) as a second-line treatment for primary biliary cholangitis (PBC) due to safety concerns. • The decision aligns with an FDA advisory committee's negative vote, citing insufficient evidence of clinical benefit and a favorable risk-benefit profile for Ocaliva. • Ocaliva remains available in the U.S. under conditional approval for PBC patients who have not responded adequately to ursodeoxycholic acid. • Conditional approval in the EU was recently revoked, but is temporarily suspended, and Ocaliva is still available, pending further review.

FDA Delays Decision on Ocaliva's Full Approval for Primary Biliary Cholangitis

• The FDA has extended its review of Intercept Pharmaceuticals' Ocaliva (obeticholic acid) for full approval in primary biliary cholangitis (PBC). • The decision was initially expected by October 15, 2024, but the FDA has not provided a new anticipated action date. • Ocaliva remains available in the U.S. under accelerated approval for PBC patients who have inadequate response or cannot tolerate UDCA. • The delay follows a negative opinion from an FDA advisory committee regarding Ocaliva's clinical benefit and risk-benefit profile.

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