Study of INT 747 in Combination With URSO in Patients With Primay Biliary Cirrhosis (PBC)

Liver Cirrhosis, Biliary Clinical Trial

Official title:

A Study of INT 747 (6α-ethyl Chenodeoxycholic Acid (6-ECDCA)) in Combination With Ursodeoxycholic Acid (URSO®, UDCA) in Patients With Primary Biliary Cirrhosis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00550862
• Other study ID #: 747-202
• Status: Terminated
• Phase: Phase 2
• Start date: October 2007
• Est. completion date: December 2010

Study information

• Verified date: January 2024
• Source: Intercept Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary hypothesis is that INT-747 will cause a reduction in alkaline phosphatase levels in Primary Biliary Cirrhosis patients, over a 12 week treatment period, as compared to placebo.

Description:

None provided

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 165
• Est. completion date: December 2010
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Male or female age 18 to 70 years.
• Stable dose of ursodeoxycholic acid (URSO, UDCA) for at least 6 months prior to screening.
• Female patients must be postmenopausal, surgically sterile, or prepared to use 2 methods of contraception with all sexual partners during the study and for 14 days after the end of dosing.
• Male patients must be prepared to use 2 methods of contraception with all sexual partners during the study and for 14 days after the end of the dosing.
• Proven or likely PBC, as demonstrated by the patient presenting with at least 2 of the

following 3 diagnostic factors:

1. History of increased AP levels for at least 6 months prior to Day 0

2. Positive AMA titer (>1:40 titer on immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive)

3. Liver biopsy consistent with PBC.

• Screening AP value between 1.5 and 10 × ULN.

Exclusion Criteria:

• Administration of the following drugs at any time during the 3 months prior to screening for the study: colchicine, methotrexate, azathioprine, or systemic corticosteroids.
• Screening conjugated (direct) bilirubin >2 × ULN.
• Screening ALT or AST >5 × ULN.
• Screening serum creatinine >1.5 mg/dL (133 mol/L).
• History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy, or poorly controlled ascites).
• History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus (HCV, HBV) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease, definite autoimmune liver disease or biopsy proven nonalcoholic steatohepatitis (NASH).
• Pregnancy.

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis
• Liver Cirrhosis, Biliary

Intervention

Drug:
• INT-747
Once a day (QD) by mouth (PO)
• Ursodeoxycholic Acid (URSO)
Stable dose for at least 6 months prior to screening. Dose as prescribed by physician.
• Placebo
Placebo

Locations

Country	Name	City	State
Austria	Karls-Franzens University	Graz
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Centre de Recherche du CHUM / University of Montreal	Montreal	Quebec
Canada	University of Toronto Western Hospital	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
France	Hopital de l'Hotel Dieu	Lyon
Germany	Johann Wolfgang Goethe University	Frankfurt
Germany	University Medical Centre Hamburg-Eppendorf	Hamburg
Germany	Medical School of Hannover	Hannover
Germany	University of Munich	Munich
Netherlands	AMC University of Amsterdam	Amsterdam
Netherlands	Erasmus Medical Centre	Rotterdam
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	University Upon Tyne/Newcastle	Newcastle Upon Tyne
United States	Tufts Medical Center	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	U Florida Hepatology	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	University of Miami - Center for Liver Diseases	Miami	Florida
United States	Beth Israel Medical Center	New York	New York
United States	Mt. Sinai School of Medicine	New York	New York
United States	Henry Ford Health Center Columbus	Novi	Michigan
United States	McGuire DVAMC	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Saint Louis University	Saint Louis	Missouri
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,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Double-blind Phase: Percent Change From Baseline in Serum Alkaline Phosphatase (ALP)	Blood samples were collected for the analysis of serum ALP. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Serum ALP, Aspartate Aminotransferase (AST), Alanine Transaminase (ALT) and Gamma-glutamyl Transferase (GGT) Levels	Blood samples were collected for the analysis of serum chemistry parameters including ALP, AST, ALT and GGT. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and at Days 15, 29, 57 and 85
Secondary	Double-blind Phase: Percent Change From Baseline in Serum ALP, AST, ALT and GGT Levels	Blood samples were collected for the analysis of serum chemistry parameters including ALP, AST, ALT and GGT. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and at Days 15, 29, 57 and 85
Secondary	LTSE Phase: Mean Percent Change From Baseline in Serum ALP, AST, ALT and GGT Levels	Blood samples were collected for the analysis of serum chemistry parameters including ALP, AST, ALT and GGT. Baseline was defined as the last observed value before the first dose of investigational product (Day 85). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and at 3, 6, 9 and 12 Months
Secondary	Double-blind Phase: Absolute Values for Albumin Levels	Blood samples were collected for the analysis of serum chemistry parameter: Albumin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and at Days 15, 29, 57 and 85
Secondary	Double-blind Phase: Percent Change From Baseline in Albumin Levels	Blood samples were collected for the analysis of serum chemistry parameter: Albumin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and at Days 15, 29, 57 and 85
Secondary	Double-blind Phase: Absolute Values for Conjugated (Direct) Bilirubin	Blood samples were collected for the analysis of serum chemistry parameter: Conjugated (Direct) bilirubin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and at Days 15, 29, 57 and 85
Secondary	Double-blind Phase: Percent Change From Baseline in Conjugated (Direct) Bilirubin	Blood samples were collected for the analysis of serum chemistry parameter: Direct bilirubin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and at Days 15, 29, 57 and 85
Secondary	LTSE Phase: Mean Percent Change From Baseline in Total and Conjugated (Direct) Bilirubin	Blood samples were collected for the analysis of serum chemistry parameters Total and direct bilirubin. Baseline was defined as the last observed value before the first dose of investigational product (Day 85). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and at 3, 6, 9 and 12 Months
Secondary	Double-blind Phase: Change From Baseline in Enhanced Liver Fibrosis (ELF) Score	Enhanced Liver Fibrosis (ELF) combines measurements of tissue inhibitor of metalloprotein-ases-1 (TIMP-1), amino-terminal pro-peptide of type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is calculated as: 2.278 + 0.851 ln (HA) + 0.751 ln (PIIINP) + 0.394 ln (TIMP-1). An ELF score of less than 7.7 indicates no to mild fibrosis; = 7.7 - < 9.8: Moderate fibrosis; = 9.8 - < 11.3: Severe fibrosis; = 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis. Higher the ELF is associated with higher fibrosis stages and greater the risk of progression. A minimum and maximum value for the scale range does not exist for this assessment. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and up to Day 85
Secondary	Double-blind Phase: Change From Baseline in HA, P3NP, and TIMP-1 Levels	Blood samples were collected for the analysis of extracellular matrix markers, including TIMP-1, PIIINP, and HA. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: C-reactive Protein	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including C-reactive protein. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: C-reactive Protein	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including C-reactive protein. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Non-essential Fatty Acid (NEFA)	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including NEFA. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: NEFA	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including NEFA. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Tumor Necrosis Factor Alpha (TNF-alpha)	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including TNF-alpha. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: TNF-alpha	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including TNF-alpha. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: TNF-beta and Tumor Growth Factor Beta (TGF-beta)	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including TNF-beta and TGF-beta. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: TNF-beta and TGF-beta	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including TNF-beta and TGF-beta. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Bile Acids and Glutathion	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including Bile acids and glutathion. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: Bile Acids and Glutathion	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including Bile acids and glutathion. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Immunoglobulin M (IgM)	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including IgM. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: IgM	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including IgM. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Osteopontin	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including Osteopontin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: Osteopontin	Blood samples were collected for the analysis of biomarkers of hepatic inflammation including Osteopontin. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Total Endogenous Bile Acids	Serum samples were collected for the analysis total endogenous bile acids. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline in Total Endogenous Bile Acids	Serum samples were collected for the analysis of total endogenous bile acids. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline is defined as post-dose visit value minus Baseline value.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Absolute Values for Fibroblast Growth Factor 19 (FGF19)	FGF-19 is a protein secreted by the gastro-intestine under farnesoid X receptor (FXR) control. Baseline was defined as the last observed value before the first dose of investigational product (Day 0).	Baseline and Up to Day 85
Secondary	Double-blind Phase: Percent Change From Baseline Values for FGF19	FGF-19 is a protein secreted by the gastro-intestine under FXR control. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Percent change from Baseline was calculated as Post Baseline minus Baseline value divided by Baseline value and multiplied by 100.	Baseline and Up to Day 85
Secondary	Double-blind Phase: Change From Baseline to Day 85 in Quality of Life as Determined by Short Form-36 (SF-36) Scale	The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the physical component summary (PCS) score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. These eight dimensions can be summarized numerically into two scores: PCS and MCS; with score range from 0=worst to 100=best, with higher scores indicating better health. Increases from baseline indicate improvement. Baseline was defined as Day 0. Change from Baseline was defined as value of post Baseline minus Baseline value.	Baseline and Up to Day 85
Secondary	LTSE Phase: Absolute Values of Quality of Life as Determined by SF-36 Scale	The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the physical component summary (PCS) score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. These eight dimensions can be summarized numerically into two scores: PCS and MCS; with score range from 0=worst to 100=best, with higher scores indicating better health. Increases from baseline indicate improvement. Baseline was defined as Day 85	Baseline and at 3, 6, 9 and 12 Months
Secondary	Double-blind Phase: Change From Baseline in Quality of Life (QoL) as Determined by Primary Biliary Cirrhosis 40 (PBC-40) Scale	PBC-40 is a disease-specific quality of life questionnaire,which consists of 5 Domains(score ranges):general symptoms (score range 7-35), itch (3-15), fatigue (11-55), cognitive function (6-30) and emotional (1-15); higher scores indicated worse outcomes.The 40 questions from the PBC-40 questionnaire were scored from 1 (lowest impact of PBC on QoL) to 5 (representing highest impact); Higher scores indicate worse quality of life. Outcomes of 'never', 'not at all' or 'strongly agree' are scored with 1, 'always', 'very much' or 'strongly disagree' with 5, with following exceptions: For questions 34-39 outcomes were scored in reverse,i.e., 'strongly agree' with 5, and 'strongly disagree' with 1. If less than 50% of the questions per domain were not answered, missing values were imputed by mean of the available question scores for that domain.If for any item multiple answers are given, most severe was used. Baseline = Day 0. Change from Baseline=post Baseline minus Baseline value.	Baseline and at Days 29, 57 and 85
Secondary	LTSE Phase: Change From Baseline in Quality of Life as Determined by PBC-40 Scale	PBC-40 is a disease-specific quality of life questionnaire, which consists of 5 Domains(score ranges):general symptoms (score range 7-35), itch (3-15), fatigue (11-55), cognitive function (6-30) and emotional (1-15); higher scores indicated worse outcomes.The 40 questions from the PBC-40 questionnaire were scored from 1 (lowest impact of PBC on QoL) to 5 (representing highest impact); Higher scores indicate worse quality of life. Outcomes of 'never', 'not at all' or 'strongly agree' are scored with 1, 'always', 'very much' or 'strongly disagree' with 5, with following exceptions: For questions 34-39 outcomes were scored in reverse,i.e., 'strongly agree' with 5, and 'strongly disagree' with 1. If less than 50% of the questions per domain were not answered, missing values were imputed by mean of the available question scores for that domain.If for any item multiple answers are given, most severe was used. Baseline = Day 85. Change from Baseline=post Baseline minus Baseline value.	Baseline and at 6 and 12 months
Secondary	Double-blind Phase: Change From Baseline in Quality of Life as Determined by 5-Dimension (5-D) Domain Scale	5-D questionnaire has 5 domains: Duration, degree, direction, disability, distribution, and total score. Single item domain scores (duration, degree, direction)=range:1-5.Disability domain has 4 items=assess impact of itching on daily activities: sleep, leisure/social activities, housework/errands, work/school;score calculated as highest score on any of 4 items; disability domain range=1-5.For distribution domain only section "Mark whether itching has been present in following parts of your body over the last 2 weeks" was used. Number of affected body parts('present') is tallied(potential sum 0-16);sum was sorted into 5 scoring bins: sum 0-2= score 1,sum 3-5=score 2,sum 6-10=score 3, sum 11-13=score 4,sum 14-16=score 5. Distribution score range reported=1-5. For all domains, higher scores=worse outcomes. Total 5D score=summing domain scores; ranges:5(no pruritus) to25 (most severe pruritus); Higher scores=worse outcomes. Baseline=Day 0.Change from Baseline=post Baseline minus Baseline	Baseline and at Days 29, 57 and 85
Secondary	Double-blind Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as any AE that started or worsened in severity on or after the first dose of study treatment.	Up to Day 85
Secondary	Double-blind Phase: Change From Baseline in Pruritus Visual Analog Scale (VAS)	A VAS questionnaire was used to assess participant's pruritus. The pruritus VAS measures participant's perception of itch on a continuous scale with score ranged from 0 = no itching and 10 = worst possible itching; higher score indicates worse outcomes. Baseline was defined as the last observed value before the first dose of investigational product (Day 0). Change from Baseline was defined as value of post Baseline minus Baseline value.	Baseline and at Days 29, 57 and 85
Secondary	LTSE Phase: Number of Participants With TEAEs and SAEs	An AE was any untoward medical occurrence in a participant administered a medicinal product without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as any AE that started or worsened in severity on or after the first dose of study treatment.	Up to 12 Months