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

Liver Cirrhosis, Biliary Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00570765
• Other study ID #: 747-201
• Secondary ID: 2007-001424-12
• Status: Completed
• Phase: Phase 2
• Start date: January 17, 2008
• Est. completion date: September 25, 2017

Study information

• Verified date: May 2021
• Source: Intercept Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 25, 2017
• Est. primary completion date: September 21, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis
• Liver Cirrhosis, Biliary

Intervention

Drug:
• Placebo
Matching placebo tablets were administered orally once daily.
• 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.

Locations

Country	Name	City	State
Austria	Karls-Franzens University	Graz
Canada	University of Alberta	Edmonton	Alberta
Canada	Centre de Recherche du CHUM / University of Montreal	Montreal	Quebec
Canada	University of Toronto	Toronto	Ontario
France	Hopital de l'Hotel Dieu	Lyon
France	Hopital Saint-Antoine	Paris
Germany	Johann Wolfgang Goethe University	Frankfurt
Germany	University Medical Centre Hamburg-Eppendorf	Hamburg
Germany	Medical School of Hannover	Hannover
Germany	University of Munich	Munich
Spain	Hospital Clinic i Provincial	Barcelona
United Kingdom	Queen Elizabeth Medical Center	Edgbaston	Birmingham
United Kingdom	Royal Infirmary	Edinburgh
United Kingdom	Royal Free Hospital	Hampstead	London
United Kingdom	John Radcliffe Hospital	Headington	Oxford
United Kingdom	Sunderland Research Ethics Committee	Jarrow
United Kingdom	University Upon Tyne/Newcastle	Newcastle Upon Tyne
United States	Henry Ford	Detroit	Michigan
United States	Baylor College of Medicine	Houston	Texas
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Virginia Mason Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Intercept Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Canada,  France,  Germany,  Spain,  United Kingdom, 

References & Publications (1)

Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Parés A, Mason A, Marschall HU, Shapiro D, Adorini L, Sciacca C, Beecher-Jones T, Böhm 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites		12 weeks
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)