Study of INT 747 in Combination With URSO in Patients With Primay Biliary Cirrhosis (PBC)
- Conditions
- Liver Cirrhosis, Biliary
- Interventions
- Registration Number
- NCT00550862
- Lead Sponsor
- Intercept Pharmaceuticals
- Brief 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.
- Detailed Description
None provided
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 165
-
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:
- History of increased AP levels for at least 6 months prior to Day 0
- Positive AMA titer (>1:40 titer on immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive)
- Liver biopsy consistent with PBC.
-
Screening AP value between 1.5 and 10 × ULN.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description INT-747 25 mg INT-747 INT-747 25 mg once daily in combination with URSO for 12 weeks. INT-747 50 mg Ursodeoxycholic Acid (URSO) INT-747 50 mg once daily in combination with URSO for 12 weeks. Placebo Ursodeoxycholic Acid (URSO) Placebo once daily in combination with URSO for 12 weeks. Placebo Placebo Placebo once daily in combination with URSO for 12 weeks. INT-747 10 mg Ursodeoxycholic Acid (URSO) INT-747 10 mg once daily in combination with URSO for 12 weeks. INT-747 25 mg Ursodeoxycholic Acid (URSO) INT-747 25 mg once daily in combination with URSO for 12 weeks. INT-747 50 mg INT-747 INT-747 50 mg once daily in combination with URSO for 12 weeks. INT-747 10 mg INT-747 INT-747 10 mg once daily in combination with URSO for 12 weeks. Placebo INT-747 Placebo once daily in combination with URSO for 12 weeks.
- Primary Outcome Measures
Name Time Method Double-blind Phase: Percent Change From Baseline in Serum Alkaline Phosphatase (ALP) Baseline and Up to Day 85 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.
- Secondary Outcome Measures
Name Time Method Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Osteopontin Baseline and Up to Day 85 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).
LTSE Phase: Mean Percent Change From Baseline in Serum ALP, AST, ALT and GGT Levels Baseline and at 3, 6, 9 and 12 Months 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.
Double-blind Phase: Absolute Values for Serum ALP, Aspartate Aminotransferase (AST), Alanine Transaminase (ALT) and Gamma-glutamyl Transferase (GGT) Levels Baseline and at Days 15, 29, 57 and 85 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).
Double-blind Phase: Absolute Values for Albumin Levels Baseline and at Days 15, 29, 57 and 85 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).
Double-blind Phase: Absolute Values for Conjugated (Direct) Bilirubin Baseline and at Days 15, 29, 57 and 85 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).
Double-blind Phase: Change From Baseline in Enhanced Liver Fibrosis (ELF) Score Baseline and up to Day 85 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.
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: NEFA Baseline and Up to Day 85 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.
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: TNF-alpha Baseline and Up to Day 85 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.
Double-blind Phase: Percent Change From Baseline in Serum ALP, AST, ALT and GGT Levels Baseline and at Days 15, 29, 57 and 85 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.
Double-blind Phase: Change From Baseline in Total Endogenous Bile Acids Baseline and Up to Day 85 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.
LTSE Phase: Change From Baseline in Quality of Life as Determined by PBC-40 Scale Baseline and at 6 and 12 months 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.
Double-blind Phase: Percent Change From Baseline in Conjugated (Direct) Bilirubin Baseline and at Days 15, 29, 57 and 85 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.
Double-blind Phase: Change From Baseline in Quality of Life (QoL) as Determined by Primary Biliary Cirrhosis 40 (PBC-40) Scale Baseline and at Days 29, 57 and 85 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.
Double-blind Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Up to Day 85 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.
Double-blind Phase: Change From Baseline in Pruritus Visual Analog Scale (VAS) Baseline and at Days 29, 57 and 85 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.
Double-blind Phase: Absolute Values for Fibroblast Growth Factor 19 (FGF19) Baseline and Up to Day 85 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).
Double-blind Phase: Percent Change From Baseline Values for FGF19 Baseline and Up to Day 85 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.
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Non-essential Fatty Acid (NEFA) Baseline and Up to Day 85 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).
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: C-reactive Protein Baseline and Up to Day 85 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.
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Tumor Necrosis Factor Alpha (TNF-alpha) Baseline and Up to Day 85 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).
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: TNF-beta and Tumor Growth Factor Beta (TGF-beta) Baseline and Up to Day 85 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).
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Bile Acids and Glutathion Baseline and Up to Day 85 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).
Double-blind Phase: Change From Baseline to Day 85 in Quality of Life as Determined by Short Form-36 (SF-36) Scale Baseline and Up to Day 85 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.
Double-blind Phase: Change From Baseline in Quality of Life as Determined by 5-Dimension (5-D) Domain Scale Baseline and at Days 29, 57 and 85 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
LTSE Phase: Number of Participants With TEAEs and SAEs Up to 12 Months 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.
LTSE Phase: Absolute Values of Quality of Life as Determined by SF-36 Scale Baseline and at 3, 6, 9 and 12 Months 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
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: TNF-beta and TGF-beta Baseline and Up to Day 85 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.
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: Osteopontin Baseline and Up to Day 85 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.
Double-blind Phase: Absolute Values for Total Endogenous Bile Acids Baseline and Up to Day 85 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).
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: Bile Acids and Glutathion Baseline and Up to Day 85 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.
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: Immunoglobulin M (IgM) Baseline and Up to Day 85 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).
Double-blind Phase: Change From Baseline Values for Biomarkers of Hepatic Inflammation: IgM Baseline and Up to Day 85 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.
Double-blind Phase: Percent Change From Baseline in Albumin Levels Baseline and at Days 15, 29, 57 and 85 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.
LTSE Phase: Mean Percent Change From Baseline in Total and Conjugated (Direct) Bilirubin Baseline and at 3, 6, 9 and 12 Months 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.
Double-blind Phase: Change From Baseline in HA, P3NP, and TIMP-1 Levels Baseline and Up to Day 85 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.
Double-blind Phase: Absolute Values for Biomarkers of Hepatic Inflammation: C-reactive Protein Baseline and Up to Day 85 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).
Trial Locations
- Locations (32)
Henry Ford Health Center Columbus
🇺🇸Novi, Michigan, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
U Florida Hepatology
🇺🇸Gainesville, Florida, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
University of Miami - Center for Liver Diseases
🇺🇸Miami, Florida, United States
Beth Israel Medical Center
🇺🇸New York, New York, United States
Saint Louis University
🇺🇸Saint Louis, Missouri, United States
Mt. Sinai School of Medicine
🇺🇸New York, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
McGuire DVAMC
🇺🇸Richmond, Virginia, United States
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
University of Toronto Western Hospital
🇨🇦Toronto, Ontario, Canada
University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Hopital de l'Hotel Dieu
🇫🇷Lyon, France
Johann Wolfgang Goethe University
🇩🇪Frankfurt, Germany
University Medical Centre Hamburg-Eppendorf
🇩🇪Hamburg, Germany
AMC University of Amsterdam
🇳🇱Amsterdam, Netherlands
Medical School of Hannover
🇩🇪Hannover, Germany
Erasmus Medical Centre
🇳🇱Rotterdam, Netherlands
University of Munich
🇩🇪Munich, Germany
Hospital Clinic i Provincial
🇪🇸Barcelona, Spain
Royal Free Hospital
🇬🇧Hampstead, London, United Kingdom
John Radcliffe Hospital
🇬🇧Headington, Oxford, United Kingdom
University Upon Tyne/Newcastle
🇬🇧Newcastle Upon Tyne, United Kingdom
Royal Infirmary
🇬🇧Edinburgh, United Kingdom
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Queen Elizabeth Medical Center
🇬🇧Edgbaston, Birmingham, United Kingdom
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Karls-Franzens University
🇦🇹Graz, Austria
Centre de Recherche du CHUM / University of Montreal
🇨🇦Montreal, Quebec, Canada
University of Calgary
🇨🇦Calgary, Alberta, Canada