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

• ClinicalTrials.gov Identifier: NCT03633227
• Recruitment Status: Terminated
• First Posted: August 16, 2018
• Results First Posted: September 6, 2022
• Last Update Posted: September 6, 2022
• Sponsor: Intercept Pharmaceuticals
• Information provided by (Responsible Party): Intercept Pharmaceuticals

Tracking Information

• First Submitted Date: April 8, 2018
• First Posted Date: August 16, 2018
• Results First Submitted Date: July 7, 2022
• Results First Posted Date: September 6, 2022
• Last Update Posted Date: September 6, 2022
• Actual Study Start Date: June 22, 2018
• Actual Primary Completion Date: July 9, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2022)

• Maximum Observed Concentration (Cmax) of Total OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. Pharmacokinetics (PK) of OCA 5 mg twice weekly or 10 mg twice weekly at Week 12 are not applicable as no participant started 5 mg twice weekly or 10 mg twice weekly at Week 12.
• Time to Maximum Concentration (Tmax) of Total OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Trough Concentration (Ctrough) of Total OCA at Week 12 [ Time Frame: 24 hours post-dose at Week 12 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 12. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Area Under the Concentration Versus Time Curve From Zero Time to 24 Hours (AUC0-24h) of Total OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Total OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Tmax of Total OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Ctrough of Total OCA at Week 18 [ Time Frame: 24 hours post-dose at Week 18 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 18. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• AUC0-24h of Total OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Total OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Tmax of Total OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Ctrough of Total OCA at Week 24 [ Time Frame: 24 hours post-dose at Week 24 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 24. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• AUC0-24h of Total OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Total OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Tmax of Total OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Ctrough of Total OCA at Week 30 [ Time Frame: 24 hours post-dose at Week 30 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 30. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• AUC0-24h of Total OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Total OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Tmax of Total OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• Ctrough of Total OCA at Week 48 [ Time Frame: 24 hours post-dose at Week 48 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 48. Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA.
• AUC0-24h of Total OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  Total OCA is molar sum of unconjugated OCA, glyco-OCA, and tauro-OCA. AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Unconjugated OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Tmax of Unconjugated OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Ctrough of Unconjugated OCA at Week 12 [ Time Frame: 24 hours post-dose at Week 12 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 12.
• AUC0-24h of Unconjugated OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  AUC0-24 was calculated using the linear/linear trapezoidal rule.
• Cmax of Unconjugated OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Tmax of Unconjugated OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Ctrough of Unconjugated OCA at Week 18 [ Time Frame: 24 hours post-dose at Week 18 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 18.
• AUC0-24h of Unconjugated OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Unconjugated OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Tmax of Unconjugated OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Ctrough of Unconjugated OCA at Week 24 [ Time Frame: 24 hours post-dose at Week 24 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 24.
• AUC0-24h of Unconjugated OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Unconjugated OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Tmax of Unconjugated OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Ctrough of Unconjugated OCA at Week 30 [ Time Frame: 24 hours post-dose at Week 30 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 30.
• AUC0-24h of Unconjugated OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Unconjugated OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Tmax of Unconjugated OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Ctrough of Unconjugated OCA at Week 48 [ Time Frame: 24 hours post-dose at Week 48 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 48.
• AUC0-24h of Unconjugated OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Cmax of Glyco Conjugate of OCA (Glyco-OCA) at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Tmax of Glyco-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Ctrough of Glyco-OCA at Week 12 [ Time Frame: 24 hours post-dose at Week 12 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 12.
• AUC0-24h of Glyco-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• Metabolite to Parent Ratio of AUC-0-24h (MRAUC) of Glyco-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  MRAUC was the ratio of AUC0-24h of Glyco-OCA (metabolite) to AUC0-24h of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of Glyco-OCA, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.
• Metabolite to Parent Ratio of Cmax (MRCmax) of Glyco-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  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.
• Cmax of Glyco-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Tmax of Glyco-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Ctrough of Glyco-OCA at Week 18 [ Time Frame: 24 hours post-dose at Week 18 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 18.
• AUC0-24h of Glyco-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Glyco-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  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 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  MRCmax was the ratio of Cmax of Glyco-OCA (metabolite) to Cmax of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of Glyco-OCA, where Cmax is the maximum observed concentration.
• Cmax of Glyco-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Tmax of Glyco-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Ctrough of Glyco-OCA at Week 24 [ Time Frame: 24 hours post-dose at Week 24 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 24.
• AUC0-24h of Glyco-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Glyco-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  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 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  MRCmax 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.
• Cmax of Glyco-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Tmax of Glyco-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Ctrough of Glyco-OCA at Week 30 [ Time Frame: 24 hours post-dose at Week 30 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 30.
• AUC0-24h of Glyco-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Glyco-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  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 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  MRCmax 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.
• Cmax of Glyco-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Tmax of Glyco-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Ctrough of Glyco-OCA at Week 48 [ Time Frame: 24 hours post-dose at Week 48 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 48.
• AUC0-24h of Glyco-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Glyco-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  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 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  MRCmax 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.
• Cmax of Tauro Conjugate of OCA (Tauro-OCA) at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Tmax of Tauro-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Ctrough of Tauro-OCA at Week 12 [ Time Frame: 24 hours post-dose at Week 12 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 12.
• AUC0-24h of Tauro-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Tauro-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  MRAUC was the ratio of AUC0-24h of Tauro-OCA (metabolite) to AUC0-24h of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of Tauro-OCA, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.
• MRCmax of Tauro-OCA at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  MRCmax was the ratio of Cmax of Tauro-OCA (metabolite) to Cmax of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of Tauro-OCA, where Cmax is the maximum observed concentration.
• Cmax of Tauro-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Tmax of Tauro-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Ctrough of Tauro-OCA at Week 18 [ Time Frame: 24 hours post-dose at Week 18 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 18.
• AUC0-24h of Tauro-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Tauro-OCA at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  MRAUC 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 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  MRCmax was the ratio of Cmax of 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.
• Cmax of Tauro-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Tmax of Tauro-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Ctrough of Tauro-OCA at Week 24 [ Time Frame: 24 hours post-dose at Week 24 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 24.
• AUC0-24h of Tauro-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Tauro-OCA at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  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 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  MRCmax 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.
• Cmax of Tauro-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Tmax of Tauro-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Ctrough of Tauro-OCA at Week 30 [ Time Frame: 24 hours post-dose at Week 30 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 30.
• AUC0-24h of Tauro-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Tauro-OCA at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  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 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  MRCmax 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.
• Cmax of Tauro-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Tmax of Tauro-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Ctrough of Tauro-OCA at Week 48 [ Time Frame: 24 hours post-dose at Week 48 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 48.
• AUC0-24h of Tauro-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of Tauro-OCA at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  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 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  MRCmax 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.
• Cmax of Glucuronide Metabolite of OCA (OCA-glucuronide) at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Tmax of OCA-glucuronide at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
• Ctrough of OCA-glucuronide at Week 12 [ Time Frame: 24 hours post-dose at Week 12 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 12.
• AUC0-24h of OCA-glucuronide at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of OCA-glucuronide at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  MRAUC was the ratio of AUC0-24h of OCA-glucuronide (metabolite) to AUC0-24h of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of OCA-glucuronide, where AUC0-24 is the area under the plasma concentration time profile from time 0 to 24 hours.
• MRCmax of OCA-glucuronide at Week 12 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12 ]
  MRCmax was the ratio of Cmax of OCA-glucuronide (metabolite) to Cmax of OCA (parent drug) * ratio of molecular weight of OCA to molecular weight of OCA-glucuronide, where Cmax is the maximum observed concentration.
• Cmax of OCA-glucuronide at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Tmax of OCA-glucuronide at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
• Ctrough of OCA-glucuronide at Week 18 [ Time Frame: 24 hours post-dose at Week 18 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 18.
• AUC0-24h of OCA-glucuronide at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of OCA-glucuronide at Week 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  MRAUC 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 18 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 18 ]
  MRCmax was the ratio of Cmax of 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 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Tmax of OCA-glucuronide at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
• Ctrough of OCA-glucuronide at Week 24 [ Time Frame: 24 hours post-dose at Week 24 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 24.
• AUC0-24h of OCA-glucuronide at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of OCA-glucuronide at Week 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  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 24 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 24 ]
  MRCmax 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 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Tmax of OCA-glucuronide at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
• Ctrough of OCA-glucuronide at Week 30 [ Time Frame: 24 hours post-dose at Week 30 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 30.
• AUC0-24h of OCA-glucuronide at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of OCA-glucuronide at Week 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  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 30 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 30 ]
  MRCmax 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 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Tmax of OCA-glucuronide at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
• Ctrough of OCA-glucuronide at Week 48 [ Time Frame: 24 hours post-dose at Week 48 ]
  Ctrough was considered as the concentration at 24-hours post-dose at Week 48.
• AUC0-24h of OCA-glucuronide at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  AUC0-24h was calculated using the linear/linear trapezoidal rule.
• MRAUC of OCA-glucuronide at Week 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  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 48 [ Time Frame: Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 48 ]
  MRCmax 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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to approximately 3 years ]
  An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. An SAE was any AE that results in death, was life-threatening, resulted in a persistent or significant disability/incapacity, resulted in in-patient hospitalization or prolonged an existing hospitalization, was a congenital anomaly/birth defect, or was an important medical event that could jeopardize the participant or could have required medical intervention to prevent one of the outcomes listed above. TEAE was defined as any AE if it met one or more of the following criteria: 1) An AE started on or after the first study drug dose and within 30 days after the last dose of study drug, 2) An AE occurred prior to the first study drug dose that worsens (increase in grade) after the first study drug dose.

Original Primary Outcome Measures (submitted: August 13, 2018)

• Evaluate maximum concentration (Cmax) of OCA, its conjugates and total OCA (sum of OCA and its conjugates) [ Time Frame: Weeks 12, 18, 24, 30 and 48: 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours at ]
• Evaluate area under the concentration curve versus time curve from 0 to 24 hours (AUC 0-24) of OCA, its conjugates and total OCA [ Time Frame: 24 hours at Day 1, and Weeks 12, 18, 24, 30, 36, and 48 ]
  Area under the concentration versus time curve from time 0 to 24 hours with measurable analyte concentration
• Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events comparing OCA to placebo [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]

Current Secondary Outcome Measures (submitted: July 7, 2022)

• Change From Baseline in the Model of End-stage Liver Disease (MELD) Score at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, 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 MELD-Sodium (Na) Score at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, 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.
• Change From Baseline in Child-Pugh Score at Day 1, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, 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 (Ascites Categories) [ Time Frame: 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.
• Number of Participants by Child-Pugh Score Component Category (Prothrombin Time Categories) [ Time Frame: 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) [ Time Frame: 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.
• Number of Participants by Child-Pugh Score Component Category (Total Bilirubin Categories) [ Time Frame: 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) [ Time Frame: 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 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Direct Bilirubin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Alkaline Phosphatase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Alanine Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Aspartate Aminotransferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Gamma Glutamyl Transferase at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Prothrombin INR at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Creatinine at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Albumin at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Platelets at Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, and 48; and Extension Months 3, 6, 9, 12, and 15 ]
• Change From Baseline in Total Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3 [ Time Frame: Baseline, 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 Total Endogenous Bile Acids Concentration at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3 [ Time Frame: Baseline, 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 3 [ Time Frame: Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3 ]
• Change From Baseline in Fibroblast Growth Factor-19 (FGF-19) Concentrations at Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3 [ Time Frame: Baseline, Weeks 6, 12, 18, 24, 30, 36, and 48; and Extension Month 3 ]

Original Secondary Outcome Measures (submitted: August 13, 2018)

• Evaluate the effect of OCA treatment compared to placebo on the model of end-stage liver disease (MELD) and its components [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  MELD Scores range from 6 [low risk] to 40 [high risk]. The three components of MELD (total bilirubin [mg/dL], serum creatinine[mg/dL], and INR) are input into the following equation to generate a MELD Score: MELD = 3.78×ln[total bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43
• Evaluate the effect of OCA treatment compared to placebo on Child-Pugh score and its components [ Time Frame: At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48 ]
  The 5 components of the Child Pugh Score are scored on a scale of 1-3 by increasing severity and then summed together to calculate the total score (range: 5 [compensated cirrhosis] - 15 [decompensated cirrhosis]). The components of the Child Pugh Score are total bilirubin [mg/dL], serum albumin [g/dL], INR, Ascites [none-severe], hepatic encephalopathy [none-grade 4]
• Evaluate the effect of OCA treatment compared to placebo on total bilirubin (mg/dL) and direct bilirubin (mg/dL) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
• Evaluate the effect of OCA treatment compared to placebo on alkaline phosphatase (U/L), alanine aminotransferase (U/L), aspartate transaminase (U/L), and gamma glutamyl transaminase (U/L) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
• Evaluate the effect of OCA treatment compared to placebo on platelets (109/L) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
• Evaluate the effect of OCA treatment compared to placebo on fibroblast growth factor-19 (pg/mL) [ Time Frame: Baseline, Screening, Day 1, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
• . Evaluate the effect of OCA treatment compared to placebo on 7α hydroxy-4-cholesten-3-one (ng/mL) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
• Evaluate the effect of OCA treatment compared to placebo on plasma bile acids (µmol/L) [ Time Frame: Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment
• Official Title: A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Liver Cirrhosis, Biliary

Intervention

• Drug: Obeticholic Acid (OCA)
  OCA will be administered per dose and schedule specified in the arm description.
  Other Names:

  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747
• Drug: Placebo
  OCA matching placebo will be administered per the schedule specified in the arm description.

Study Arms

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

Publications *

• Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906. No abstract available.
• European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6. No abstract available.
• Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. doi: 10.1002/hep.27210. Epub 2014 Jul 8. No abstract available.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 30, 2021): 22
• Original Estimated Enrollment (submitted: August 13, 2018): 50
• Actual Study Completion Date: July 9, 2021
• Actual Primary Completion Date: July 9, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Estonia, Germany, Hungary, Italy, Lithuania, Spain, United States

Administrative Information

• NCT Number: NCT03633227
• Other Study ID Numbers: 747-401
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Intercept Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Intercept Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Steven Shiff, M.D.; Intercept Pharmaceuticals

• PRS Account: Intercept Pharmaceuticals
• Verification Date: August 2022