Study of INT-747 as Monotherapy in Participants With Primary Biliary Cirrhosis (PBC)

A Study of INT-747 (6-ECDCA) Monotherapy in Patients With Primary Biliary Cirrhosis

The primary hypothesis was that obeticholic acid (OCA) will cause a reduction in alkaline phosphatase levels in PBC participants, over a 12-week treatment period, as compared to placebo.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis, Biliary
• Intervention / Treatment: Drug: Placebo; Drug: Obeticholic Acid (OCA)

Detailed Description

The study included 2 phases: a 3-month randomized, double-blind (DB), placebo-controlled, parallel group phase, followed by a long-term safety extension (LTSE). The planned duration of the LTSE phase was country-specific, ranging from 108 months to indefinitely. On-site visits occurred at least every 6 months.

Following completion of the 3-month DB phase, participants who continued to meet protocol requirements were given the opportunity to enroll in the LTSE phase of the study at selected study sites. The participants who enrolled in the LTSE phase started OCA administration, from a starting dose (10 or 50 milligrams [mg]) based on the dose of OCA or placebo received in the DB phase or on the timing of entry into the LTSE phase.

Because the LTSE phase was not planned in the original study design, participants had varied gaps between the end of the DB phase and the start of the LTSE phase. Moreover, some participants initiated ursodeoxycholic acid during the course of that break.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Karls-Franzens University
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1K8
      • University of Alberta
  • Ontario
    • Toronto, Ontario, Canada, M5T 1S8
      • University of Toronto
  • Quebec
    • Montreal, Quebec, Canada, H2L 3R4
      • Centre de Recherche du CHUM / University of Montreal
• France
  • Lyon, France, 69288
    • Hopital de l'Hotel Dieu
  • Paris, France, 75012
    • Hopital Saint-Antoine
• Germany
  • Frankfurt, Germany, 60590
    • Johann Wolfgang Goethe University
  • Hamburg, Germany, 20246
    • University Medical Centre Hamburg-Eppendorf
  • Hannover, Germany, 30625
    • Medical School of Hannover
  • Munich, Germany, 81377
    • University of Munich
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic I Provincial
• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Royal Infirmary
  • Jarrow, United Kingdom, NE32 3DT
    • Sunderland Research Ethics Committee
  • Newcastle Upon Tyne, United Kingdom, NE2 4HH
    • University Upon Tyne/Newcastle
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom, B15 2TH
      • Queen Elizabeth Medical Center
  • London
    • Hampstead, London, United Kingdom, NW3 2QG
      • Royal Free Hospital
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 9DU
      • John Radcliffe Hospital
• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98105
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Female participants must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use 1 effective method of contraception with all sexual partners during the study and for 14 days after the end of dosing.
• Male participants must be prepared to use 1 effective method of contraception with all sexual partners during the study during the study unless they had a prior vasectomy.
• Proven or likely PBC, as demonstrated by the participant presenting with at least 2 of the following 3 diagnostic factors:
• History of increased alkaline phosphatase (ALP) levels for at least 6 months;
• Positive antimitochondrial antibody titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive);
• Liver biopsy consistent with PBC
• Screening ALP level between 1.5 and 10 × upper limit of normal (ULN).

Exclusion Criteria:

• Administration of the following drugs at any time during the 3 months prior to screening for the study: ursodeoxycholic acid, colchicine, methotrexate, azathioprine, or systemic corticosteroids.
• Screening conjugated (direct) bilirubin >2 × ULN.
• Screening alanine aminotransferase or aspartate aminotransferase >5 × ULN.
• Screening serum creatinine >133 micromoles/liter (1.5 mg/deciliter).

History or presence of hepatic decompensation (for example, variceal bleeds, encephalopathy, or poorly controlled ascites).

• History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus infection, primary sclerosing cholangitis, alcoholic liver disease, definite autoimmune liver disease or biopsy proven nonalcoholic steatohepatitis.
• Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DB OCA 10 mg; OCA 10 mg for 3 months during the DB phase.	Drug: Obeticholic Acid (OCA); Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.; Other Names: INT-747; 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
Experimental: DB OCA 50 mg; OCA 50 mg for 3 months during the DB phase.	Drug: Obeticholic Acid (OCA); Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.; Other Names: INT-747; 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
Placebo Comparator: DB OCA Placebo; Matching placebo for 3 months during the DB phase.	Drug: Placebo; Matching placebo tablets were administered orally once daily.
Experimental: LTSE OCA Total; After completion of the 3-month DB phase, all eligible participants were offered the opportunity to enter an open-label LTSE for up to 96 months beginning at 10 mg OCA. Doses up to 50 mg daily were evaluated.	Drug: Obeticholic Acid (OCA); Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.; Other Names: INT-747; 6α-ethyl-chenodeoxycholic acid (6-ECDCA)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85	The percent change in serum ALP from baseline to Day 85 is reported. The baseline value used was the mean of the pretreatment Screening and Day 0 evaluations.	Baseline, Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85	As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to Day 85 is reported.	Baseline, Day 85
DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85	As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to Day 85 is reported.	Baseline, Day 85
DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites		12 weeks
DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85	As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to Day 85 is reported.	Baseline, Day 85
LTSE Phase: Median Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit	The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months)
LTSE Phase: Mean Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit	The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months)
LTSE: Median Percent Change In GGT From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Mean Percent Change In GGT From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Median Percent Change In ALT From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Mean Percent Change In ALT From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Median Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Mean Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Median Percent Change In Total Bilirubin From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)
LTSE: Mean Percent Change In Total Bilirubin From Baseline To Last Available Visit	As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.	Baseline (DB), Last Available Visit (up to 96 months)

Collaborators and Investigators

• Sponsor: Intercept Pharmaceuticals
• Investigators: Study Chair: Christian Weyer, MD, Intercept Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Pares A, Mason A, Marschall HU, Shapiro D, Adorini L, Sciacca C, Beecher-Jones T, Bohm O, Pencek R, Jones D; Obeticholic Acid PBC Monotherapy Study Group. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018 May;67(5):1890-1902. doi: 10.1002/hep.29569. Epub 2018 Jan 29.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2008
• Primary Completion (Actual): September 21, 2010
• Study Completion (Actual): September 25, 2017

Study Registration Dates

• First Submitted: December 7, 2007
• First Submitted That Met QC Criteria: December 7, 2007
• First Posted (Estimate): December 11, 2007

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Gastrointestinal Agents; Cathartics; Chenodeoxycholic Acid
• Other Study ID Numbers: 747-201; 2007-001424-12 (EudraCT Number)