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

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.

Time frame: Baseline and at Days 15, 29, 57 and 85

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).

Time frame: Baseline and at Days 15, 29, 57 and 85

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.

Time frame: Baseline and at Days 15, 29, 57 and 85

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.

Time frame: Baseline and at 3, 6, 9 and 12 Months

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.

Time frame: Baseline and up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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).

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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.

Time frame: Baseline and Up to Day 85

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

Time frame: Baseline and at 3, 6, 9 and 12 Months

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.

Time frame: Baseline and at Days 29, 57 and 85

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.

Time frame: Baseline and at 6 and 12 months

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

Time frame: Baseline and at Days 29, 57 and 85

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.

Time frame: Up to Day 85

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.

Time frame: Baseline and at Days 29, 57 and 85

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.

Time frame: Up to 12 Months