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

Primary Purpose

Liver Cirrhosis, Biliary

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Placebo
Obeticholic Acid (OCA)
Sponsored by
Intercept Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liver Cirrhosis, Biliary

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Henry Ford
  • Baylor College of Medicine
  • Virginia Commonwealth University
  • Virginia Mason Medical Center
  • Karls-Franzens University
  • University of Alberta
  • University of Toronto
  • Centre de Recherche du CHUM / University of Montreal
  • Hopital de l'Hotel Dieu
  • Hopital Saint-Antoine
  • Johann Wolfgang Goethe University
  • University Medical Centre Hamburg-Eppendorf
  • Medical School of Hannover
  • University of Munich
  • Hospital Clinic i Provincial
  • Queen Elizabeth Medical Center
  • Royal Free Hospital
  • John Radcliffe Hospital
  • Royal Infirmary
  • Sunderland Research Ethics Committee
  • University Upon Tyne/Newcastle

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Arm Label

DB OCA 10 mg

DB OCA 50 mg

DB OCA Placebo

LTSE OCA Total

Arm Description

OCA 10 mg for 3 months during the DB phase.

OCA 50 mg for 3 months during the DB phase.

Matching placebo for 3 months during the DB phase.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
December 7, 2007
Last Updated
May 28, 2021
Sponsor
Intercept Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00570765
Brief Title
Study of INT-747 as Monotherapy in Participants With Primary Biliary Cirrhosis (PBC)
Official Title
A Study of INT-747 (6-ECDCA) Monotherapy in Patients With Primary Biliary Cirrhosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
January 17, 2008 (Actual)
Primary Completion Date
September 21, 2010 (Actual)
Study Completion Date
September 25, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Intercept Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Cirrhosis, Biliary

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DB OCA 10 mg
Arm Type
Experimental
Arm Description
OCA 10 mg for 3 months during the DB phase.
Arm Title
DB OCA 50 mg
Arm Type
Experimental
Arm Description
OCA 50 mg for 3 months during the DB phase.
Arm Title
DB OCA Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo for 3 months during the DB phase.
Arm Title
LTSE OCA Total
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo tablets were administered orally once daily.
Intervention Type
Drug
Intervention Name(s)
Obeticholic Acid (OCA)
Other Intervention Name(s)
INT-747, 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
Intervention Description
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.
Primary Outcome Measure Information:
Title
DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85
Description
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.
Time Frame
Baseline, Day 85
Secondary Outcome Measure Information:
Title
DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85
Description
As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to Day 85 is reported.
Time Frame
Baseline, Day 85
Title
DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85
Description
As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to Day 85 is reported.
Time Frame
Baseline, Day 85
Title
DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites
Time Frame
12 weeks
Title
DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85
Description
As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to Day 85 is reported.
Time Frame
Baseline, Day 85
Title
LTSE Phase: Median Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit
Description
The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
Time Frame
Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months)
Title
LTSE Phase: Mean Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit
Description
The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
Time Frame
Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months)
Title
LTSE: Median Percent Change In GGT From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Mean Percent Change In GGT From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Median Percent Change In ALT From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Mean Percent Change In ALT From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Median Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Mean Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Median Percent Change In Total Bilirubin From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)
Title
LTSE: Mean Percent Change In Total Bilirubin From Baseline To Last Available Visit
Description
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.
Time Frame
Baseline (DB), Last Available Visit (up to 96 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christian Weyer, MD
Organizational Affiliation
Intercept Pharmaceuticals, Inc.
Official's Role
Study Chair
Facility Information:
Facility Name
Henry Ford
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
Virginia Mason Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Karls-Franzens University
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1K8
Country
Canada
Facility Name
University of Toronto
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 1S8
Country
Canada
Facility Name
Centre de Recherche du CHUM / University of Montreal
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2L 3R4
Country
Canada
Facility Name
Hopital de l'Hotel Dieu
City
Lyon
ZIP/Postal Code
69288
Country
France
Facility Name
Hopital Saint-Antoine
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Johann Wolfgang Goethe University
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
University Medical Centre Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Medical School of Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
University of Munich
City
Munich
ZIP/Postal Code
81377
Country
Germany
Facility Name
Hospital Clinic i Provincial
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Queen Elizabeth Medical Center
City
Edgbaston
State/Province
Birmingham
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
Royal Free Hospital
City
Hampstead
State/Province
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
John Radcliffe Hospital
City
Headington
State/Province
Oxford
ZIP/Postal Code
OX3 9DU
Country
United Kingdom
Facility Name
Royal Infirmary
City
Edinburgh
ZIP/Postal Code
EH16 4SA
Country
United Kingdom
Facility Name
Sunderland Research Ethics Committee
City
Jarrow
ZIP/Postal Code
NE32 3DT
Country
United Kingdom
Facility Name
University Upon Tyne/Newcastle
City
Newcastle Upon Tyne
ZIP/Postal Code
NE2 4HH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
29023915
Citation
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.
Results Reference
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Study of INT-747 as Monotherapy in Participants With Primary Biliary Cirrhosis (PBC)

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